Inhibitors of retroviral proteases

ABSTRACT

The present invention relates to a compound of the formula ##STR1## in which A, Q, R 2 , R 3  and R 4 , and also the corresponding, asterisked radicals, are defined as indicated in the description, to a process for their preparation, and also to their use for inhibiting retroviral proteases.

The present invention relates to substances which inhibit the action ofretroviral proteases, to a process for their preparation and to theiruse, and also to pharmaceuticals containing these substances.

The etiological cause of acquired immune deficiency syndrome (AIDS) isthe so-called human immunodeficiency virus (HIV) (F. Barre-Sinoussi etal., Science 220, (1983), 868-870; R. C. Gallo et al., Science 224,(1984), 500-502; R. C. Gallo and L. Montagnier, Scient. Am. 259(4),(1988), 40-48). HIV is a retrovirus and is included in the lentivirusgroup (M. A. Gonda, F. Wong-Staal and R. C. Gallo, Science, 227, (1985),173; P. Sonigo et al., Gell, 42, (1985), 369).

The AIDS epidemic has by now spread, to a greater or lesser extent, tovirtually all countries. The World Health Organization (WHO) estimatesthe number of infected adults worldwide to be about 8-10 million (WeeklyEpidemiological Record, World Health Organization, Geneva, 1991, 66,353-357). Of these, more than 1 million already have AIDS and a furthermillion have developed serious infection-related diseases. 1 millionchildren have been born who have been infected by their mothers and, ofthese children, about half have already developed AIDS or have died. WHOcalculates that in the year 2000 roughly 30-40 million people will beinfected.

While the sole substance hitherto licensed for the indication AIDS,zidovudine (AZT), is able to prolong patient life in many cases, itpossesses serious, toxic side effects which in many cases requiretherapy to be discontinued. Strains of HIV have already been discoveredwhich exhibited significantly less sensitivity to AZT and thus gave riseto the development of resistance. Further approaches to HIV therapy aretherefore urgently required.

In analogy with proteins of other retroviruses, HIV proteins areinitially translated as long, precursor gag, pol and env polyproteins(C. Dickson et al., in RNA Tumor Viruses (Editors: R. Weiss, N. Teich,H. Varmus and J. Coffin) 2nd Ed., revised, pages 513-648, Cold SpringHarbor Laboratory, Cold Spring Harbor, N.Y.) and are only subsequentlyprocessed proteolytically to form the structural proteins (p17 (MA), p24(CA), p7 (NC) and p6), the enzymes (protease (PR), reverse transcriptase(RT) and integrase (IN)), and the coat proteins (gp120 (SU) and gp41(TM)) (Nomenclature: J. Leis et al., J. Virol, 62, (1988), (1808-1809)).It is assumed that the cleavage of the gag and pol polyproteins isbrought about by a virally encoded protease. Mutations within the regionencoding the protease give rise to non-infectious virus particles (N. E.Kohl et al. Proc. Natl. Acad. Sci. USA 85, (1988), (4686-4690)).

The HIV protease is composed of 99 amino acids and evidently excisesitself out of the pol polyprotein by hydrolyzing the two Phe-Pro bondsin positions 68-69 and 167-168, respectively (M. C. Graves, J. J. Lim,E. P. Heimer and R. A. Kramer Proc. Natl. Acad. Sci. USA 85 (1988);2449-2453; J. Hansen, S. Billich, T. Schulze, S. Sukrow and K. Molling,EMBO J. 7 (1988), 1785-1791; E. P. Lillehoj et al., J. Virology 62(1988) 3053-3058; J. Schneider and S. B. H. Kent, Cell 54 (1988)363-368).

Some inhibitors of the HIV protease are already known from theliterature. The first representative was pepstatin A, which has an IC₅₀value of approximately 0.5 mmol/l (I. Katoh, T. Yasunaga, Y. Ikawa andY. Yoshinaka, Nature, 329, (1987), 654-656). Since then, some otherinhibitors have been described (see, for example, B. A. G. Tomaselli etal., Chim. Oggi 9(5), (1991), 6027, EP 0428849, EP 0435059).

A novel structural class has now been found which is highly active ininhibiting the HIV protease in an enzyme test.

The present invention relates to compounds of the formula ##STR2## c1.1)in which Q is a radical of the formula IIa or IIb ##STR3## Y is oxygenor sulfur, and A is a radical of the formula IV and A* is a radical ofthe formula IV*,

    D--(E)n--F(o)--(G)p--                                      (IV)

    D*--(E*)n*--(F*)o*--(G*)p*--                               (IV*)

where

E, E*, F, F*, G and G*, independently of each other, are a natural orunnatural amino acid, azaamino acid or imino acid;

n, n*, o, o*, p and p*, independently of each other, are 0 or 1;

D is R¹ or a radical of the formulae V, VI or VII, and

D* is R¹ * or a radical of the formulae V*, VI* or VII*, ##STR4## and inwhich R¹ and R¹ *, independently of each other, a1) are

hydrogen,

carboxyl,

(C₁ -C₁₈)-alkyl, which is optionally unsaturated once or twice and whichis optionally substituted by up to 3 identical or different radicalsfrom the group

mercapto,

hydroxyl,

(C₁ -C₇)-alkoxy,

carbamoyl,

(C₁ -C₈)-alkanoyloxy,

carboxyl,

(C₁ -C₇)-alkoxycarbonyl,

F, Cl, Br, I,

amino,

amidino, which can be optionally substituted by one, two or three (C₁-C₈)-alkyl radicals,

guanidino, which can be optionally substituted by one or twobenzyloxycarbonyl radicals or by one, two, three or four (C₁ -C₈)-alkylradicals,

(C₁ -C₇)-alkylamino,

di-(C₁ -C₇)-alkylamino,

(C₁ -C₆)-alkoxycarbonylamino,

(C₇ -C₁₅)-aralkoxycarbonyl,

(C₇ -C₁₅)-aralkoxycarbonylamino,

phenyl-(C₁ -C₄)-alkoxy,

9-fluorenylmethoxycarbonylamino,

(C₁ -C₆)-alkylsulfonyl,

(C₁ -C₆)-alkylsulfinyl,

(C₁ -C₆)-alkylthio,

hydroxyamino,

hydroxyimino,

sulfamoyl,

sulfo,

carboxamido,

formyl,

hydrazono,

imino,

phenyl,

a radical CONR¹² R¹³ or CONR¹² *R¹³ *,

by up to six hydroxyl, or

by up to five (C₁ -C₈)-alkanoyloxy;

monocyclic, bicyclic or tricyclic (C₃ -C₁₈)-cycloalkyl,

(C₃ --C₁₈)-cycloalkyl-(C₁ -C₆)-alkyl

where the cycloalkyl moiety is in each case optionally substituted byone or two identical or different radicals from the group

F, Cl, Br, I,

carboxyl,

carbamoyl,

carboxymethoxy,

hydroxyl,

(C₁ -C₇)-alkoxy,

(C₁ -C₇)-alkyl,

(C₁ -C₇)-alkyloxycarbonyl,

amino,

(C₁ -C₆)-alkylamino-(C₁ -C₆)-alkyl,

di-(C₁ -C₆)-alkylamino-(C₁ -C₆)-alkyl,

amidino,

hydroxyamino,

hydroxyimino,

hydrazono,

imino,

guanidino,

(C₁ -C₆)-alkoxysulfonyl,

(C₁ -C₆)-alkoxysulfinyl,

(C₁ -C₆)-alkoxycarbonylamino,

(C₆ -C₁₂)-aryl-(C₁ -C₄)-alkoxycarbonylamino,

(C₁ -C₇)-alkylamino,

di-(C₁ -C₇)-alkylamino, and

trifluoromethyl;

(C₆ -C₁₄)-aryloxy-(C₁ -C₆)-alkyl,

(C₆ -C₁₄)-aryl,

(C₆ -C₁₄)-aryl-(C₁ -C₆)-alkyl, or

(C₆ -C₁₄)-aryl-(C₃ -C₈)-cycloalkyl, in which the aryl moiety is in eachcase optionally substituted by one, two or three identical or differentradicals from the group

F, Cl, Br, I,

hydroxyl,

mono-, di- or trihydroxy-(C₁ -C₄)-alkyl,

trifluoromethyl,

formyl,

carboxamido,

mono- or di-(C₁ -C₄)-alkylaminocarbonyl,

nitro,

(C₁ -C₇)-alkoxy,

(C₁ -C₇)-alkyl,

(C₁ -C₇)-alkoxycarbonyl,

amino,

(C₁ -C₇)-alkylamino,

di-(C₁ -C₇)-alkylamino,

carboxyl,

carboxymethoxy,

amino-(C₁ -C₇)-alkyl,

(C₁ -C₇)-alkylamino-(C₁ -C₇)-alkyl,

di-(C₁ -C₇)-alkylamino-(C₁ -C₇)-alkyl,

(C₁ -C₇)-alkoxycarbonylmethoxy,

carbamoyl,

sulfamoyl,

(C₁ -C₇)-alkoxysulfonyl,

(C₁ -C₈)-alkylsulfonyl,

sulfo-(C₁ -C₈)-alkyl,

guanidino-(C₁ -C₈)-alkyl and

(C₁ -C₆)-alkoxycarbonylamino;

Het,

Het-(C₁ -C₆)-alkyl,

Het-(C₃ -C₈)-cycloalkyl,

Het-(C₃ -C₈)-cycloalkyl-(C₁ -C₄)-alkyl,

Het-(C₃ -C₈)-cycloalkoxy-(C₁ -C₄)-alkyl,

Het-thio-(C₁ -C₆)-alkyl,

Het-thio-(C₃ -C₈)-cycloalkyl,

Het-thio-(C₃ -C₈)-cycloalkyl-(C₁ -C₄)-alkyl, where Het is in each casethe radical of a 5- to 7-membered monocyclic or 8- to 10-memberedbicyclic ring system which can be benzofused, aromatic, partiallyhydrogenated or completely hydrogenated, which can contain, asheteroelements, one, two, three or four different radicals from thegroup N, O, S, NO, SO, and SO₂, which can be substituted by 1 to 6hydroxyl and which is optionally monosubstituted, disubstituted ortrisubstituted as defined for (C₆ -C₁₄)-aryl under a1) and/or by oxo, orare a radical NR¹² R¹³ or NR¹² *R¹³ *, respectively, or,

a2)

are a radical of the formula VIII or VIII*, respectively,

    R1a--W                                                     (VIII)

    R1a*--W                                                    (VIII*)

in which R1a and R1a* are defined as are R1 and R1*, respectively, undera1) and W or W* is --CO--, --CS--, O--CO--, --SO₂ --, --SO--, --S--,--NHSO₂ --, --NHCO--, --CH(OH)--, --N(OH)-- or --CO--V--, where V is apeptide having from 1 to 10 amino acids;

or in which R¹ and R¹ *, independently of each other, form, togetherwith R¹¹ or R¹¹ *, respectively, and the atoms carrying the latter,monocyclic or bicyclic, saturated or partially unsaturated, ring systemshaving 5-12 ring members which, in addition to carbon, can also contain1 sulfur atom which can optionally be oxidized to the sulfoxide orsulfone;

a3)

are a glycosyl radical, preferably a glucofuranosyl or glucopyranosylradical, which is derived from naturally occurring aldotetroses,aldopentoses, aldohexoses, ketopentoses, ketohexoses, deoxyaldoses,aminoaldoses and oligosaccharides and also their stereoisomers;

R² and R² *,

independently of each other, are defined as are R¹ and R¹ *,respectively, under a1) or a2), or form, together with R⁴ or R⁴ *,respectively, and the atoms carrying the latter, monocyclic or bicyclic,saturated or partially unsaturated, ring systems having from 5 to 12ring members, or form, together with R³ or R³ *, respectively, and theatoms carrying the latter, cyclic, saturated or partially unsaturated,ring systems having from 3 to 12 ring members;

R³ and R³ *, independently of each other, are

hydrogen or

(C₁ -C₃)-alkyl;

R⁴ and R⁴ *, independently of each other, are

hydrogen or

(C₁ -C₈)-alkyl;

R⁵ is

hydrogen,

(C₁ -C₂₀)-alkyl,

(C₂ -C₂₀)-alkenyl or alkynyl,

(C₇ -C₂₀)-arylalkyl or (C₆ -C₂₀)-aryl,

(C₃ -C₈)-cycloalkyl which can be optionally substituted by differentradicals from the group hydroxyl, alkoxy, carboxyl, alkanoyloxy,alkoxycarbonyl, F, Cl, Br, I, amino, alkylamino or dialkylamino;

an equivalent of a pharmaceutically tolerated cation,

or

is a phosphinate prodrug;

R⁶ is oxygen or sulfur;

R⁷ and R⁷ *, independently of each other, are

hydrogen,

(C₁ -C₂₀)-alkyl,

(C₂ -C₂₀)-alkenyl or alkynyl, (C₆ -C₂₀)-aryl,

(C₇ -C₂₀)-arylalkyl, which can be optionally substituted by differentradicals from the group hydroxyl, alkoxy, carboxyl, alkanoyloxy,alkoxycarbonyl, F, Cl, Br, I, amino, alkylamino or dialkylamino,

or, together, can form a ring having 2-6 carbon atoms,

R⁸ and R⁸ *, independently of each other, are

hydrogen or

(C₁ -C₈)-alkyl, or,

together with R⁹ or R⁹ *, respectively, and the atoms carrying thelatter, form monocyclic or bicyclic, saturated or partially unsaturated,ring systems having 5-12 ring members;

R⁹ and R⁹ *

are, independently of each other, defined as are R¹ and R¹ *,respectively, under a1), are hydroxyl or (C₁ -C₈)-alkanoyloxy, or form,together with R¹⁰ or R¹⁰ *, respectively, and the atoms carrying thelatter, cyclic, saturated or partially unsaturated, ring systems havingfrom 3 to 12 ring members;

or

form, together with R¹¹ or R¹¹ *, respectively, and the atoms carryingthe latter, a monocyclic or bicyclic, saturated or partiallyunsaturated, ring system having 5-12 ring members which, in addition tocarbon, can also contain 1 sulfur atom which can optionally be oxidizedto the sulfoxide or sulfone; or can contain 1 nitrogen atom, where thering system can optionally be substituted by amino;

R¹⁰ and R¹⁰ *, independently of each other, are

hydrogen or

(C₁ -C₆)-alkyl;

R¹¹ and R¹¹ *, independently of each other, are

hydrogen,

hydroxyl,

(C₁ -C₄)-alkanoyloxy, or

(C₁ -C₈)-alkyl;

R¹², R¹² *, R¹³ and R¹³ *, independently of each other, are

hydrogen,

(C₁ -C₈)-alkyl which can be substituted by

amino,

(C₁ -C₄)-alkylamino,

di-(C₁ -C₄)-alkylamino,

mercapto,

carboxyl,

hydroxyl or

(C₁ -C₄)-alkoxy,

(C₃ -C₇)-cycloalkyl,

(C₁ -C₄)-alkoxycarbonyl,

(C₆ -C₁₄)-aryl, (C₆ -C₁₄)-aryl-(C₁ -C₄)-alkoxycarbonyl which can besubstituted in the aryl moiety as described for R¹ or R¹ *,

Het or

Het-(C₁ -C₄)-alkyl, where Het is defined as described for R¹ or R¹ *,

or where R¹² and R¹³ or R¹² * and R¹³ *, respectively, form, togetherwith the nitrogen a toms carrying them, monocyclic or bicyclic,saturated, partially unsaturated or aromatic ring systems which alsocontain, as further ring members in addition to carbon, 1 or 2 nitrogenatoms, 1 sulfur atom or 1 oxygen atom, and which can be substituted by(C₁ -C₄)-alkyl,

where

in the above compounds of the formula I, one or more amide groups(--CONH--) of the main chain can be replaced by --CH₂ NR¹⁴ --, --CH₂S--, --CH₂ O--, --OCH₂ --, --CH₂ CH₂ --, --CH═CH-- (cis and trans),--COCH₂ --, --CH(OH)CH₂ --, --CH₂ SO--, --CH₂ SO₂ --, --COO--,--P(O)(OR¹⁵)CH₂ -- and --P(O) (OR¹⁵)NH--, or even by an amide grouphaving reverse polarity (--NHCO--);

in which R¹⁴ and R¹⁵, independently of each other, are

hydrogen or

(C₁ -C₄)-alkyl;

and the physiologically tolerated salts thereof.

The nomenclature employed in this description follows general practicein the case of amino acids, that is the amino group is located on theleft, and the carboxyl group on the right, of each amino acid. This alsoapplies, in a corresponding manner, for azaamino acids and imino acids.

Natural or unnatural amino acids can, if chiral, be present in the D orL form. α-Amino acids are preferred. The following may be mentioned byway of example:

Aad, Abu, γAbu, ABz, 2ABz, εAca, Ach, Acp, Adpd, Ahb, Aib, βAib, Ala,βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze,Azi, Bai, Bph, Can, Cit, Cys, (Cys)2, Cyta, Daad, Dab, Dadd, Dap, Dapm,Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln,hGlu, His, hlle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr,Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, βLys,ΔLys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg,Pic, Pro, ΔPro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi,βThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, Nal, Tbg, Npg,Chg, Thia, (cf. e.g. Houben-Weyl, Methoden der organischen Chemie[Methods of organic chemistry], Volume XV/1 and 2, Stuttgart, 1974):

Azaamino acids are natural or unnatural amino acids where the centralstructural component --CHR-- or CH₂ -- is replaced by --NR-- or --NH--,respectively.

An imino acid is generally understood to mean a natural or unnaturalamino acid whose amino group is monosubstituted. In this connection,particular mention may be made of compounds which are substituted by (C₁-C₈)-alkyl which, in turn, is optionally substituted as described for C₁-C₁₈ -alkyl under a1). Heterocycles from the following group also comeinto consideration:

Pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid;1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylicacid; decahydroquinoline-2-carboxylic acid;octahydrocyclopenta[b]pyrrole-2-carboxylic acid;2-azabicyclo[2.2.2]octane-3-carboxylic acid; 2-azabicyclo[2.2.1]heptane-3-carboxylic acid; 2-azabicyclo-[3.1.0]hexane-3-carboxylic acid;2-azaspiro[4.4]nonane-3-carboxylic acid;2-azaspiro[4.5]decane-3-carboxylic acid;spiro[(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid];spiro[(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid];2-azatricyclo[4.3.0.1⁶,9 ]-decane-3-carboxylic acid;decahydrocyclohepta[b]pyrrole-2-carboxylic acid;decahydrocycloocta[b]pyrrole-2-carboxylic acid;octahydrocyclopenta[c]pyrrole-2-carboxylic acid;octahydroisoindole-1-carboxylic acid;2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid;2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid;tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid;pyrazolidine-3-carboxylic acid; hydroxyproline-2-carboxylic acid; all ofwhich can optionally be substituted by one of the following radicals:##STR5## Glycosyl radicals as described above are derived, inparticular, from natural D-monosaccharides or L-monosaccharides whichoccur in microorganisms, plants, animals or humans, such as ribose(Rib), arabinose (Ara), xylose (Xyl), lyxose (Lyx), allose (All),altrose (Alt), glucose (Glc), mannose (Man), gulose (Gul), idose (Ido),galactose (Gal), talose (Tal), erythrose (Ery), threose (Thr), psicose(Psi), fructose (Fru), sorbose (Sor), tagarose (Tag), xylulose (Xyu),fucose (Fuc), rhamnose (Rha), olivose (Oli), oliose (Olo), mycarose(Myc), rhodosamine (RN), N-acetylglucosamine (GlcNAc),N-acetylgalactosamine (GalNAc) or N-acetylmannosamine (ManNAc), ordisaccharides, such as maltose (Mal), lactose (Lac), cellobiose (Cel),gentibiose (Gen), N-acetyllactosamine (LacNAc), chitobiose (Chit),β-galactopyranosyl-(1-3)-N-acetylgalactosamine andβ-galactopyranosyl-(1-3)- or -(1-4)-N-acetylglucosamine, and also theirsynthetic derivatives, such as 2-deoxy-, 2-amino-, 2-acetamido- or2-halo-, preferably bromo- and iodo-sugars.

The centers of chirality in the compounds of the formula (I) can havethe R configuration, the S configuration or the R, S configuration.

Alkyl can be straight-chain or branched. This also applies in acorresponding manner to radicals derived from alkyl, such as, forexample, alkoxy, alkylthio, alkylamino, dialkylamino, alkanoyl andaralkyl.

Cycloalkyl is also understood to mean alkyl-substituted radicals, suchas, for example, 4-methylcyclohexyl or 2,3-dimethylcyclopentyl.

Bicycloalkyl or tricycloalkyl is understood to mean an isocyclic,aliphatic, non-aromatic radical which can optionally containunsymmetrically distributed double bonds and can also optionally besubstituted by open-chain aliphatic side chains. The two or three ringswhich are components of such a radical are fused or spiro-linked andlinked via a ring C atom or a side-chain C atom. Examples of theseradicals are bornyl, norbornyl, pinanyl, norpinanyl, caranyl,norcaranyl, thujanyl, adamantyl, bicyclo[3.3.0]octyl,bicyclo[4.4.0]decyl, bicyclo[1.1.0]butyl or spiro[3.3]heptylsubstituents.

If the said cycles carry more than one substituent, the substituents canthen be located cis or trans in relation to each other.

Examples of (C₆ -C₁₄)-aryl are phenyl, naphthyl, biphenylyl orfluorenyl; phenyl and naphthyl are preferred. This also applies in acorresponding manner to radicals derived therefrom, such as, forexample, aryloxy, aroyl, aralkyl and aralkoxy. Aralkyl is understood tomean an unsubstituted or substituted (C₆ -C₁₄)-aryl radical which islinked to (C₁ -C₆)-alkyl, such as, for example, benzyl, 1-naphthylmethylor 2-naphthylmethyl, without, however, aralkyl being restricted to thesaid radicals.

Within the meaning of the above definition, Het radicals are pyrrolyl,furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, cinnolinyl or β-carbolinyl, or a benzofused,cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivative ofthese radicals.

These heterocycles can be substituted on a nitrogen atom by oxides; (C₁-C₇)-alkyl, e.g. methyl or ethyl; phenyl; phenyl-(C₁ -C₄)-alkyl, e.g.benzyl; and/or on one or more carbon atoms by (C₁ -C₄)-alkyl, e.g.methyl; phenyl; phenyl-(C₁ -C₄)-alkyl, e.g. benzyl; halogen; hydroxyl;(C₁ -C₄)-alkoxy, e.g. methoxy, phenyl-(C₁ -C₄)-alkoxy, e.g. benzyloxy,or oxo, or be partially or completely saturated.

Examples of radicals of this type are 2- or 3-pyrrolyl; phenyl-pyrrolyl,e.g. 4- or 5-phenyl-2-pyrrolyl; 2-furyl; 2-thienyl; 4-imidazolyl;methyl-imidazolyl, e.g. 1-methyl-2-, 4- or 5-imidazolyl;1,3-thiazol-2-yl; 2-, 3- or 4-pyridyl; 1-oxido-2-, 3- or 4-pyridino;2-pyrazinyl; 2-, 4- or 5-pyrimidinyl; 2-, 3- or 5-indolyl; substituted2-indolyl, e.g. 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-,5-chloro- or 4,5-dimethyl-2-indolyl; 1-benzyl-2- or 3-indolyl;4,5,6,7-tetrahydro-2-indolyl; cyclohepta[b]-5-pyrrolyl; 2-, 3- or4-quinolyl; 1-, 3- or 4-isoquinolyl; 1-oxo-1,2,dihydro-3-isoquinolyl;2-quinoxalinyl; 2-benzofuranyl; 2-benzoxazolyl; benzothiazolyl;benz[e]indol-2-yl or β-carbolin-3-yl.

Examples of partially hydrogenated or completely hydrogenatedheterocyclic rings are dihydropyridinyl; pyrrolidinyl, e.g. 2-, 3- or4-N-methylpyrrolidinyl; piperazinyl; morpholino; thiomorpholino;tetrahydrothiophenyl; benzodioxolanyl.

Halogen is fluorine, chlorine, bromine or iodine, in particular fluorineor chlorine.

Salts of compounds of the formula (I) are understood to mean, inparticular, pharmaceutically utilizable or non-toxic salts.

Such salts are formed, for example, from compounds of the formula (I)which contain acidic groups, e.g. carboxyl in addition, using alkalimetals or alkaline earth metals, such as, for example, Na, K, Mg and Ca,and also using physiologically tolerated organic amines, such as, forexample, triethylamine and tris(2-hydroxyethyl)amine.

Compounds of the formula I which contain basic groups, e.g. an aminogroup or a guanadino group, form salts with inorganic acids, such as,for example, hydrochloric acid, sulfuric acid or phosphoric acid, andwith organic carboxylic or sulfonic acids, such as, for example, aceticacid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaricacid and p-toluenesulfonic acid.

Phosphinate prodrugs are described, for example, in H. Bundgaard,"Design of Prodrugs", Elsevier, Amsterdam 1985, pp. 70ff. Examples ofsuch prodrug forms are glyceryl esters, 1,2-difatty acid glyceryltriesters, O-acyloxyalkyl esters and 1-methyl-2-nitroethyl esters.

Preferred pharmaceutically tolerated cations are sodium, potassium,magnesium, aluminum, lithium, ammonium and triethylammonium.

Compounds of the formula I are preferred in which, c1.2) the radicalsand symbols with and without asterisk are in each case identical.

Furthermore, compounds of the formula I are particularly preferred inwhich, c1.3)

Q is a radical of the formulae IIa or IIb;

Y is oxygen or sulfur;

A, A*, D, D*, n, n*, o, o*, p and p* are defined as above;

E, E*, F, F*, G and G*, independently of each other, are a natural orunnatural α-amino acid or α-imino acid;

R¹ and R¹ *, independently of each other, a1*) are

hydrogen;

carboxyl,

(C₁ -C₁₂)-alkyl, which is optionally unsaturated once and which isoptionally substituted by up to 2 identical or different radicals fromthe group

hydroxyl,

(C₁ -C₄)-alkoxy,

carbamoyl,

(C₁ -C₈)-alkanoyloxy,

carboxyl,

(C₁ -C₄)-alkoxycarbonyl,

F,

amino,

(C₁ -C₇)-alkylamino,

di-(C₁ -C₇)-alkoxycarbonylamino,

benzyloxycarbonyl,

benzyloxycarbonylamino,

9-fluorenylmethoxycarbonylamino,

(C₁ -C₄)-alkylsulfonyl,

a radical CONR¹² R¹³ or CONR¹² *R¹³ *,

by up to three phenyl,

by up to six hydroxyl, or

by up to four (C₁ -C₈)-alkanoyloxy;

monocyclic or bicyclic (C₃ -C₁₂)-cycloalkyl,

(C₃ -C₁₂)-cycloalkyl-(C₁ -C₆)-alkyl where the cycloalkyl moiety is ineach case optionally substituted by one or two identical or differentradicals from the group

F,

carboxyl,

hydroxyl,

(C₁ -C₇)-alkoxy,

(C₁ -C₄)-alkyl,

(C₁ -C₄)-alkyloxycarbonyl,

amino,

(C₁ -C₆)-alkoxycarbonylamino,

benzyloxycarbonylamino,

(C₁ -C₄)-alkylamino, and

di-(C₁ -C₄)-alkylamino;

(C₆ -C₁₀)-aryloxy-(C₁ -C₆)alkyl,

(C₆ -C₁₀)-aryl,

(C₆ -C₁₀)-aryl-(C₁ -C₆)-alkyl, in which the aryl moiety is in each caseoptionally substituted by one, two or three identical or differentradicals from the group

F, Cl, Br,

hydroxyl,

hydroxy-(C₁ -C₄)-alkyl,

carboxamido,

mono- or di-(C₁ -C₄)-alkylaminocarbonyl,

(C₁ -C₄)-alkoxy,

(C₁ -C₄)-alkyl,

(C₁ -C₄)-alkoxycarbonyl,

amino,

(C₁ -C₄)-alkylamino,

di-(C₁ -C₄)-alkylamino,

carboxyl,

carbamoyl,

(C₁ -C₄)-alkoxycarbonylamino;

Het,

Het-(C₁ -C₆)-alkyl,

Het-(C₅ -C₆)-cycloalkyl,

Het-thio-(C₁ -C₄)-alkyl,

Het-thio-(C₅ -C₆)-cycloalkyl, where Het is in each case the radical of a5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring systemwhich can be aromatic, partially hydrogenated or completelyhydrogenated, which can contain, as heteroelements, one, two, three orfour different radicals from the group N, O, S, NO, SO and SO₂, whichcan be substituted by 1 to 4 hydroxyl, and which is optionallymonosubstituted or disubstituted as defined for (C₆ -C₁₀)-aryl under a1)and/or by oxo,

or is a radical NR¹² R¹³ or NR¹² *R¹³ *, respectively, or

a2*)

are a radical of the formula VIII or VIII*, respectively,

    R1a--W                                                     (VIII)

    R1a*--W*                                                   (VIII*)

in which R1a and R1a* are defined as are R¹ and R1*, respectively, undera1*) and W or W* is --CO--, --O--CO--, --SO₂ --, --SO--, --S--, --NHCO--or --CH(OH)--;

or in which R¹ and R¹ *, independently of each other form, together withR11 or R11*, respectively, and the atoms carrying the latter,monocyclic, saturated or partially unsaturated, ring systems having 5-8ring members which, in addition to carbon, can also contain 1 sulfuratom which can optionally be oxidized to the sulfoxide or sulfone;

a3*)

are a glycosyl radical which is defined as above;

R² and R² *, independently of each other,

b1*) are

hydrogen,

carboxyl,

(C₁ -C₁₀)-alkyl which is optionally unsaturated once or twice and whichis optionally substituted by up to 3 identical or different radicalsfrom the group

hydroxyl,

(C₁ -C₇)-alkoxy,

(C₁ -C₇)-alkylthio,

(C₁ -C₇)-alkylsulfinyl,

(C₁ -C₇)-alkylsulfonyl,

(C₁ -C₇)-alkanoyloxy,

carboxyl,

(C₁ -C₇)-alkoxycarbonyl,

Cl, Br,

amino,

amidino,

guanidino,

N,N'-di-(benzyloxycarbonyl)-guanidino,

carbamoyl,

(C₇ -C₁₅)-aralkoxycarbonyl,

(C₁ -C₅)-alkoxycarbonylamino,

(C₇ -C₁₅)-aralkoxycarbonylamino, or

9-fluorenylmethoxycarbonylamino;

(C₃ -C₁₂)-cycloalkyl,

(C₃ -C₁₂)-cycloalkyl-(C₁ -C₃)-alkyl,

(C₆ -C₁₄)-aryl,

(C₆ -C₁₄)-aryl-(C₁ -C₃)-alkyl, where the aryl moiety is in each caseoptionally substituted by one, two or three identical or differentradicals from the group

F, Cl, Br, I,

hydroxyl,

(C₁ -C₇)-alkoxy,

(C₁ -C₇)-alkyl,

(C₁ -C₇)-alkoxycarbonyl,

amino and

trifluoromethyl; or

Het-(C₁ -C₆)-alkyl, where Het is the radical of a 5- or 6-memberedmonocyclic or 9- to 10-membered bicyclic, optionally partially orcompletely hydrogenated, heteroaromatic compound, having at least 1 Catom, 1-4 N atoms and/or 1-2 S atoms and/or 1-2 O atoms as ring members,which is optionally monosubstituted or disubstituted as described forthe aryl moiety under a1); or

b2*) form, together with R⁴ or R⁴ *, respectively, and the atomscarrying the latter, pyrrolidine or piperidine which can in each casealso be fused with cyclopentyl, cyclohexyl or phenyl,

or form, together with R³ or R³ *, respectively, and the atoms carryingthe latter, cyclic, saturated or partially unsaturated, ring systemshaving 3-8 ring members;

R³ and R³ *, independently of each other, are

hydrogen,

methyl or

ethyl;

R⁴ and R⁴ *, independently of each other, are

hydrogen,

(C₁ -C₄)-alkyl;

R⁵ is

hydrogen,

(C₁ -C₆)-alkyl,

(C₂ -C₆)-alkenyl or alkynyl,

(C₇ -C₂₀)-arylalkyl, (C₆ -C₁₀)-aryl,

an equivalent of a pharmaceutically tolerated cation or

is glyceryl ester,

1,2-difatty acid glyceryl triester, O-acyloxyalkylester or

1-methyl-2-nitroethyl ester,

R⁶ is

oxygen or sulfur;

R⁷ is defined as described under A1),

R⁸ and R⁸ *, independently of each other, are

hydrogen,

(C₁ -C₈)-alkyl or form, together with R⁹ or R⁹ *, respectively, and theatoms carrying the latter, pyrrolidine or piperidine which can in eachcase be additionally fuzed with cyclopentyl, cyclohexyl or phenyl;

R⁹ and R⁹ *,

independently of each other, are defined as are R² and R² *,respectively, under b1), or are

(C₁ -C₈)-alkanoyloxy, or form, together with R¹⁰ or R¹⁰ *, respectively,and the atoms carrying the latter, cyclic, saturated or partiallyunsaturated, ring systems having from 5 to 12 ring members; or

form, together with R¹¹ or R¹¹ *, respectively, and the atoms carryingthe latter, a monocyclic or bicyclic, saturated or partiallyunsaturated, ring system having 5-12 ring members which, in addition tocarbon, can also contain 1 sulfur atom which can optionally be oxidizedto the sulfoxide or sulfone;

R¹⁰ and R¹⁰ *, independently of each other, are

hydrogen or

(C₁ -C₄)-alkyl;

R¹¹ and R¹¹ *, independently of each other, are

hydrogen,

hydroxyl,

(C₁ -C₄)-alkanoyloxy or

(C₁ -C₄)-alkyl;

R¹², R¹² *, R¹³ and R¹³ *, independently of each other, are

hydrogen,

(C₁ -C₈)-alkyl which can be substituted by

amino,

(C₁ -C₄)-alkylamino,

di-(C₁ -C₄)-alkylamino,

carboxyl,

hydroxyl or

(C₁ -C₄)-alkoxy,

(C₁ -C₄)-alkoxycarbonyl,

(C₆ -C₁₀)-aryl which can be substituted as described for R¹ or R¹ *,respectively

(C₆ -C₁₀)-aryl-(C₁ -C₄)-alkoxycarbonyl,

Het or

Het-(C₁ -C₄)-alkyl, where Het is defined as described for R¹ or R¹ *,respectively,

where,

in the above compounds of the formula I, one or more amide groups(--CONH--) of the main chain can be replaced by a group comprising --CH₂NR¹⁴ --, --CH₂ O--, --OCH₂ --, --CH₂ CH₂ --, --COCH₂ --, --CH(OH)CH₂ --or --COO--, or else by an amide group having reversed polarity(--NHCO--);

R¹⁴ is

hydrogen or

(C₁ -C₄)-alkyl;

and the physiologically tolerated salts thereof.

Compounds of the formula I are particularly preferred in which,

c1.4)

Q is a radical of the formulae IIa or IIb;

Y, A, A*, D, D*, n, n*, o and o* are defined as above,

p and p are 1;

R¹ and R¹ *, independently of each other, are

hydrogen,

carboxyl,

(C₁ -C₁₀)-alkyl,

(C₃ -C₈)-cycloalkyl,

(C₃ -C₈)-cycloalkyl-(C₁ -C₁₀)-alkyl,

phenyl-(C₁ -C₈)-alkyl which can be substituted in the phenyl moiety asdescribed for aryl under a1*),

triphenyl-(C₁ -C₄)-alkyl,

optionally protected mono- or di-amino-(C₁ -C₁₀)-alkyl or amino-(C₆-C₁₀)-aryl-(C₁ -C₄)-alkyl or amino-(C₃ -C₁₀)-cycloalkyl-(C₁ -C₄)-alkyl,such as

2-amino-3-phenylpropyl,

mono-, di-, tri-, tetra-, penta- or hexa-hydroxy-(C₁ -C₁₀)-alkyl or-alkanoyl,

(C₁ -C₄)-alkoxy-(C₁ -C₁₀)-alkyl,

(C₁ -C₄)-alkoxycarbonyl-(C₁ -C₁₀)-alkyl,

(C₁ -C₈)-alkylsulfonyl,

(C₁ -C₈)-alkylsulfinyl,

mono-, di- or tri-hydroxy-(C₁ -C₈)-alkylsulfonyl,

mono-, di- or tri-hydroxy-(C₁ -C₈)-alkylsulfinyl,

mono-, di-, tri- or tetra-(C₁ -C₈)-alkanoyloxy-(C₁ -C₁₀)-alkyl,

(C₁ -C₁₁)-alkanoyl,

optionally protected amino-(C₁ -C₁₁)-alkanoyl,

di-(C₁ -C₇)-alkylamino (C₂ -C₁₁)-alkanoyl,

(C₁ -C₉)-cycloalkylcarbonyl,

amino-substituted (C₃ -C₉)-cycloalkylcarbonyl,

amino-substituted (C₃ -C₉)-cycloalkylsulfonyl,

(C₆ -C₁₀)-aryloxy-(C₂ -C₇)-alkanoyl,

(C₆ -C₁₀)-aryl-(C₂ -C₇)-alkanoyl,

benzoyl, benzenesulfonyl or (C₆ -C₁₀)-aryl-(C₁ -C₄)-alkylcarbonyl or-sulfonyl which is optionally substituted by amino, halogen, (C₁-C₇)-alkyl, (C₁ -C₇)-alkoxy or (C₁ -C₇)-alkoxycarbonyl,

(C₁ -C₁₀)-alkoxycarbonyl,

substituted (C₁ -C₁₀)-alkoxycarbonyl, such as

2-(trimethylsilyl)ethoxycarbonyl,

2,2,2-trichloroethoxycarbonyl or

1,1-dimethyl-2,2,2-trichloroethoxycarbonyl,

(C₆ -C₁₄)-aryl-(C₁ -C₆)-alkoxycarbonyl,

(C₆ -C₁₀)-aryl-(C₁ -C₈)-alkyl, (C₃ -C₁₀)-cycloalkyl-(C₁ -C₈)-alkyl or(C₁ -C₁₀)-alkyl which are substituted by optionally protected amino orhydroxyl, such as

2-amino-1-hydroxy-4-methylpentyl,

9-fluorenylmethoxycarbonyl,

ketohexosyl,

ketopentosyl,

deoxyhexoketosyl,

deoxypentoketosyl,

aldohexosyl,

aldopentosyl,

deoxyhexoaldosyl,

deoxypentoaldosyl,

2-amino-2-deoxyhexosyl,

2-acetamido-2-deoxyhexosyl,

lactosyl or

maltosyl where the linked sugars can be present in the pyranose orfuranose form,

Het-(C₁ -C₆)-alkyl,

Het-carbonyl or -sulfonyl,

Het-(C₁ -C₆)-alkylcarbonyl or -sulfonyl,

Het-mercapto-(C₁ -C₆)alkylcarbonyl or -sulfonyl,

where Het is in each case

furyl, thienyl, benzothienyl, benzodioxolanyl, pyrrolyl, imidazolyl,isoxazolyl, thiazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazinyl, pyrrolidyl, piperidyl, piperazinyl,morpholino, thiomorpholino, tetrahydrofuryl, tetrahydropyryl,tetrahydrothienyl, indolyl, quinolyl or isoquinolyl, where theseradicals can also be substituted by one or two identical or differentradicals from the group

(C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, (C₁ -C₄)-alkoxycarbonyl, (C₁-C₄)-alkoxycarbonylamino, hydroxyl, amino, mono- or di-(C₁-C₄)-alkylamino and oxido;

R² and R² *,

independently of each other, are

hydrogen,

carboxyl,

(C₁ -C₈)-alkyl which is optionally substituted by up to 2 identical ordifferent radicals from the group

hydroxyl,

(C₁ -C₄)-alkoxy,

(C₁ -C₄)-alkylthio,

(C₁ -C₄)-alkylsulfinyl,

(C₁ -C₄)-alkylsulfonyl,

(C₁ -C₄)-alkanoyloxy,

carboxyl,

(C₁ -C₄)-alkoxycarbonyl,

amino,

amidino,

guanidino,

N,N'-di-(benzyloxycarbonyl)-guanidino,

carbamoyl,

(C₆ -C₁₀)-aryl-(C₁ -C₃)-alkoxycarbonyl,

(C₁ -C₅)-alkoxycarbonylamino,

(C₆ -C₁₀)-aryl-(C₁ -C₃)-alkoxycarbonylamino, or

(C₃ -C₁₀)-cycloalkyl,

(C₃ -C₁₀)-cycloalkyl-(C₁ -C₃)-alkyl,

(C₁ -C₄)-alkyl-(C₃ -C₁₀)-cycloalkyl-(C₁ -C₃)-alkyl,

(C₆ -C₁₀)-aryl,

(C₆ -C₁₀)-aryl-(C₁ -C₃)-alkyl where the aryl moiety is in each caseoptionally substituted by one, two or three identical or differentradicals from the group

F, Cl, Br,

hydroxyl,

(C₁ -C₄)-alkoxy,

(C₁ -C₄)-alkyl,

(C₁ -C₄)-alkoxycarbonyl and

amino, or

Het-(C₁ -C₄)-alkyl where Het is defined as in the case of R¹ or R¹ *,respectively;

R³ and R³ *, independently of each other, are

hydrogen or

methyl;

R⁴ and R⁴ *, independently of each other, are

hydrogen or

methyl;

R⁵, R⁶ and R⁷ are defined as described above under c1.3);

R⁸ and R⁸ *, independently of each other, are

hydrogen,

methyl, ethyl or n-propyl, or form, together with R⁹ or R⁹ *,respectively, and the atoms carrying the latter, a1,2,3,4-tetrahydroisoquinoline or a 2-azabicyclooctane skeleton;

R⁹ and R⁹ *, independently of each other, are defined as are R² or R² *,respectively, or

are (C₁ -C₈)-alkanoyloxy or form, together with R.sup. 10 or R¹⁰ *,respectively, and the atoms carrying the latter, cyclic ring systemshaving from 5 to 7 ring members;

or form, together with R¹¹ or R¹¹ *, a thiochromane system whose sulfuratom can optionally be oxidized to the sulfone;

R¹⁰ and R¹⁰ *, independently of each other, are

hydrogen or

methyl;

R¹¹ and R¹¹ * are defined as under c1.3);

where,

in the above compounds of the formula 1, one or more amide groups(--CONH--) of the main chain can be replaced as defined above under A3);

R¹⁴ is

hydrogen or

methyl;

and the physiologically tolerated salts thereof.

Compounds of the formula I are furthermore particularly preferred

in which c1.5),

Q is a radical of the formula IIa;

R¹ and R¹ *, independently of each other, are

hydrogen,

carboxyl,

(C₁ -C₈)-alkylsulfonyl, such as

methylsulfonyl,

tert-butylsulfonyl or

isopropylsulfonyl,

(C₁ -C₈)-alkylsulfinyl,

(C₁ -C₈)-mono-, di- or tri-hydroxyalkylsulfonyl, such as

2-hydroxyethylsulfonyl or

2-hydroxypropylsulfonyl,

hydroxy-(C₁ -C₁₀)-alkanoyl, such as

2-hydroxypropionyl,

3-hydroxypropionyl,

3-hydroxybutyryl or

2-hydroxy-3-methylbutyryl,

mono-, di-, tri- or tetra-hydroxy-(C₁ -C₄)-alkyl, such as

1,2,3-trihydroxypropyl,

1,2-dihydroxyethyl or

hydroxymethyl,

(C₁ -C₈)-alkanoyloxy-(C₁ -C₁₀)-alkyl, such as

acetoxymethyl,

1,2-diacetoxyethyl,

1,2,3-triacetoxypropyl,

(C₁ -C₁₁)-alkanoyl, such as

n-decanoyl,

formyl,

acetyl,

propionyl,

pivaloyl,

isovaleryl or

isobutyryl,

amino-(C₁ -C₁₁)-alkanoyl, such as

3-amino-3,3-dimethylpropionyl,

5,4-aminobutyryl,

5-aminopentanoyl,

6-aminohexanoyl,

N-(C₁ -C₄)-alkoxycarbonylamino-(C₁ -C₈)-alkyl, such as

4-N-tert-butoxycarbonylaminobutyryl,

5-N-tert-butoxycarbonylaminopentanoyl,

6-N-tert-butoxycarbonylaminohexanoyl,

di-(C₁ -C₇)-alkylamino-(C₂ -C₁₁)-alkanoyl, such as

dimethylaminoacetyl,

(C₃ -C₉)-cycloalkylcarbonyl, such as

cyclopropylcarbonyl,

cyclobutylcarbonyl,

cyclopentylcarbonyl or

cyclohexylcarbonyl,

amino-(C₃ -C₈)-cycloalkylcarbonyl, such as

2-aminocyclopropylcarbonyl,

3-aminocyclobutylcarbonyl,

3-aminocyclopentylcarbonyl,

4-aminocyclohexylcarbonyl,

amino-(C₃ -C₈)-cycloalkylsulfonyl, such as

3-aminocyclopentylsulfonyl,

4-aminocyclohexylsulfonyl,

phenyl

triphenyl-(C₁ -C₂)-alkyl, such as

triphenylmethyl,

2-triphenylethyl,

(C₆ -C₁₀)-aryl-(C₁ -C₄)-alkyl, such as

benzyl,

2-phenylethyl or

1-naphthylmethyl,

(C₆ -C₁₀)-aryl-(C₂ -C₇)-alkanoyl, such as

phenylacetyl,

phenylpropanoyl or

phenylbutanoyl,

(C₆ -C₁₀)-aryloxy-(C₂ -C₇)-alkanoyl, such as

1-naphthyloxyacetyl or

phenyloxyacetyl,

benzoyl or -benzenesulfonyl which are optionally substituted by halogen,amino, (C₁ -C₇)-alkyl, (C₁ -C₇)-alkoxy or (C₁ -C₇)-alkoxycarbonyl, suchas

4-chlorobenzoyl,

4-methylbenzoyl,

2-methoxycarbonylbenzoyl,

4-methoxybenzoyl,

benzenesulfonyl,

4-methylphenylsulfonyl,

benzylsulfonyl, benzylsulfinyl or benzylthio which are optionallysubstituted by halogen, amino, (C₁ -C₇)-alkyl, (C₁ -C₇)-alkoxy or (C₁-C₇)-alkoxycarbonyl, such as

4-chlorobenzylsulfonyl,

benzylsulfinyl,

4-chlorobenzylthio,

amino,

(C₁ -C₄)-alkoxycarbonylamino,

(C₁ -C₁₂)-alkanoyl which is substituted by hydroxyl or amino andoptionally by phenyl or cyclohexyl, such as

2-amino-1-hydroxy-4-methylpentyl,

(C₆ -C₁₀)-aryl- or (C₃ -C₁₀)-cycloalkyl-(C₁ -C₄)-alkyl or (C₁ -C₈)-alkylwhich are substituted by optionally protected amino, such as

2-amino-3-phenylpropyl or

N-tert-butoxycarbonyl-2-amino-3-phenylpropyl,

(C₁ -C₁₀)-alkoxycarbonyl, such as

methoxycarbonyl,

ethoxycarbonyl,

isobutoxycarbonyl or

tert-butoxycarbonyl,

substituted (C₁ -C₁₀)-alkoxycarbonyl, such as

2-(trimethylsilyl)ethoxycarbonyl,

2,2,2-trichloroethoxycarbonyl,

1,1-dimethyl-2,2,2-trichloroethoxycarbonyl,

(C₆ -C₁₄)-aryl-(C₁ -C₆)-alkoxycarbonyl, such as

benzyloxycarbonyl,

1- or 2-naphthylmethoxycarbonyl or

9-fluorenylmethoxycarbonyl,

1-deoxyhexoketosyl or 1-deoxypentoketosyl, such as

1-deoxyfructos-1-yl, 1-deoxysorbos-1-yl or

1-deoxyribulos-1-yl

hexosyl or pentosyl, such as

mannosyl, glucosyl or galactosyl,

xylosyl, ribosyl or arabinosyl,

6-deoxyhexosyl, such as

rhamnosyl, fucosyl or deoxyglucosyl,

aminosugar residues, such as

2-amino-2-deoxyglucosyl,

2-acetamido-2-deoxyglucosyl,

2-amino-2-deoxygalactosyl or

2-acetamido-2-deoxygalactosyl,

lactosyl,

maltosyl,

where the linked sugars can be present in the pyranose or the furanoseform,

Het, such as

2-pyridyl,

4-pyridyl or -4-(N-oxidopyridyl),

Het-carbonyl or Het-sulfonyl, such as

piperidino-4-carbonyl,

morpholino-4-carbonyl,

pyrrolyl-2-carbonyl,

pyridyl-3-carbonyl,

4-tert-butoxycarbonylamino-1-piperidylcarbonyl,

4-amino-1-piperidylcarbonyl,

4-tert-butoxycarbonylamino-1-piperidylsulfonyl,

4-amino-1-piperidylsulfonyl,

Het-(C₁ -C₆)-alkyl, such as

2-pyridyl-(C₁ -C₆)-alkyl,

3-pyridyl -(C₁ -C₆)-alkyl,

4-pyridyl-(C₁ -C₆)-alkyl,

Het-(C₁ -C₆)-alkanoyl or Het-(C₁ -C₆)-alkylsulfonyl, such as

2-pyridyl-(C₁ -C₆)-alkanoyl,

3-pyridyl-(C₁ -C₆)-alkanoyl,

4-pyridyl-(C₁ -C₆)-alkanoyl,

2-pyridyl-(C₁ -C₆)-alkylsulfonyl,

Het-mercapto-(C₁ -C₃)-alkylcarbonyl, such as

2-pyridylthioacetyl,

where Het is in each case

pyrrolyl,

imidazolyl,

pyridyl,

pyrimidyl,

pyrrolidyl,

piperidyl,

quinolyl,

isoquinolyl or

morpholino,

where the latter can also be substituted by one or two identical ordifferent radicals from the group (C₁ -C₄)-alkyl, (C₁-C₄)-alkoxycarbonyl, (C₁ -C₄)-alkoxycarbonylamino, hydroxyl, amino ormono- or di-(C₁ -C₄)-alkylamino;

R² and R² *, independently of each other, are

hydrogen,

carboxyl,

methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, pentylor hexyl,

cyclohexyl,

cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl,

4-methylcyclohexylmethyl,

1-decahydronaphthylmethyl or 2-decahydronaphthylmethyl,

phenyl,

benzyl,

2-phenylethyl,

1-naphthylmethyl or 2-naphthylmethyl,

2-methylbenzyl, 3-methylbenzyl or 4-methylbenzyl,

2,4,6-trimethylbenzyl,

4-tert-butylbenzyl,

4-tert-butoxybenzyl,

4-hydroxybenzyl,

4-methoxybenzyl,

2,4-dimethoxybenzyl,

3,4-dihydroxybenzyl,

3,4-dimethoxybenzyl,

(benzodioxolan-4-yl)methyl,

4-chlorobenzyl,

hydroxymethyl,

1-hydroxyethyl,

2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl or

2-(4-pyridyl)ethyl,

2-thienylmethyl or 3-thienylmethyl,

2-(2-thienyl)ethyl or 2-(3-thienyl)ethyl,

indol-2-ylmethyl or indol-3-ylmethyl,

(1-methylimidazol-4-yl)methyl,

imidazol-4-ylmethyl or imidazol-1-ylmethyl,

2-thiazolylmethyl,

3-pyrazolylmethyl,

4-pyrimidylmethyl,

2-benzo[b]thienylmethyl or 3-benzo[b]thienylmethyl,

2-furylmethyl,

2-(methylthio)ethyl,

2-(methylsulfinyl)ethyl,

2-(methylsulfonyl)ethyl,

R³, R³ *, R⁴, R⁴ *, R¹⁰ and R¹⁰ * are

hydrogen;

R⁵ is

hydrogen,

(C₁ -C₆)-alkyl or

an equivalent of a pharmaceutically tolerated cation;

R⁶ is

oxygen;

R⁸ and R⁸ *, independently of each other, are

hydrogen or

form, together with R⁹ or R⁹ *, respectively, and the atoms carrying thelatter, a 1,2,3,4-tetrahydroisoquinoline or 2-azabicyclooctane skeleton;

R⁹ and R⁹ *, independently of each other, are defined as are R² or R² *,respectively, or are

hydroxyl,

acetoxy,

tert-butoxymethyl,

3-guanidinopropyl,

carbamoylmethyl or carbamoylethyl,

carboxymethyl or carboxyethyl,

mercaptomethyl,

(1-mercapto-1-methyl)ethyl,

aminomethyl, 2-aminoethyl, 3-aminopropyl or 4-aminobutyl,

N, N-dimethylamino,

N,N'-di(benzyloxycarbonyl)guanidinopropyl,

2-benzyloxycarbonylethyl, benzyloxycarbonylmethyl ortert-butylsulfonylmethyl or

4-benzylcarbonylaminobutyl;

R¹¹ and R¹¹ *, independently of each other, are

hydrogen,

hydroxyl or

acetoxy;

where,

in the above compounds of this invention, one or more amide groups(--CONH--) of the main chain can be replaced by --CH₂ NR¹⁴ -- or--CH(OH)CH₂ --;

R¹⁴ is

hydrogen or

methyl;

and the physiologically tolerated salts thereof.

Compounds of the formula I are very particularly preferred,

c1.6), in which Q is a radical of the formula IIa;

R¹ and R¹ *, independently of each other, are

hydrogen,

carboxyl,

(C₁ -C₈)-alkylsulfonyl, such as

methylsulfonyl,

tert-butylsulfonyl or

isopropylsulfonyl,

(C₁ -C₈)-mono- or di-hydroxyalkylsulfonyl, such as

2-hydroxyethylsulfonyl or

2-hydroxypropylsulfonyl,

mono-, di- or tri-hydroxy-(C₁ -C₃)-alkyl, such as

1,2,3-trihydroxypropyl,

1,2-dihydroxyethyl or

hydroxymethyl,

(C₁ -C₈)-alkanoyl, such as

butanoyl,

(C₆ -C₁₀)-aryloxy-(C₁ -C₄)-alkanoyl, such as

1- or 2-naphthyloxyacetyl,

(C₆ -C₁₀)-aryl-(C₁ -C₄)-alkanoyl, such as

1- or 2-naphthylacetyl,

(C₁ -C₈)-alkoxycarbonyl, such as

methoxycarbonyl,

ethoxycarbonyl,

isobutoxycarbonyl or

tert-butoxycarbonyl,

(C₆ -C₁₀)-aryl-(C₁ -C₄)-alkoxycarbonyl, such as

benzyloxycarbonyl or

1- or 2-naphthylmethoxycarbonyl,

9-fluorenylmethoxycarbonyl,

(C₁ -C₄)-alkanoyloxy-(C₁ -C₆)-alkyl, such as

acetoxymethyl,

1,2-diacetoxyethyl,

1,2,3-triacetoxypropyl,

phenyl,

triphenylmethyl,

(C₆ -C₁₀)-aryl-(C₁ -C₄)-alkyl, such as

benzyl,

benzenesulfonyl which is optionally substituted by halogen, amino, (C₁-C₄)-alkyl or methoxy, such as

benzenesulfonyl,

4-methlylphenylsulfonyl,

benzylsulfonyl, benzylsulfinyl or benzylthio which is optionallysubstituted by halogen, amino, (C₁ -C₄)-alkyl or methoxy, such as

4-chlorobenzylsulfonyl,

benzylsulfinyl or

4-chlorobenzylthio,

Het, such as 2- or 4-pyridyl or

4-(N-oxidopyridyl),

Het-carbonyl or Het-sulfonyl, such as

4-tert-butoxycarbonylamino-1-piperidylcarbonyl,

4-amino-1-piperidylcarbonyl,

2-quinolylcarbonyl,

4-tert-butoxycarbonylamino-1-piperidylsulfonyl,

4-amino-1-piperidylsulfonyl,

Het-(C₁ -C₄)-alkylsulfonyl, such as

2-(4-pyridyl)-ethylsulfonyl,

Het-(C₁ -C₄)-alkanoyl, such as

2-pyridylacetyl or

3-pyridylacetyl,

Het-mercapto-(C₁ -C₃)-alkylcarbonyl, such as

2-pyridylthioacetyl,

where Het is in each case

pyrrolyl,

imidazolyl,

pyridyl,

pyrimidyl,

pyrrolidyl,

piperidyl,

quinolyl,

isoquinolyl or

morpholino,

where this radical can also be substituted by one or two identical ordifferent radicals from the group methyl, amino and (C₁-C₄)-alkoxycarbonylamino,

amino-(C₃ -C₆)-cycloalkylcarbonyl, such as

2-aminocyclopropylcarbonyl,

3-aminocyclobutylcarbonyl,

3-aminocyclopentylcarbonyl,

4-aminocyclohexylcarbonyl,

(C₁ -C₈)-alkanoyl which is substituted by hydroxyl and amino andoptionally by phenyl or cyclohexyl, such as

2-amino-1-hydroxy-4-methylpentyl,

phenyl- or cyclohexyl-(C₁ -C₆)-alkyl which is substituted by optionallyprotected amino, such as

2-amino-3-phenylpropyl or

N-tert-butoxycarbonyl-2-amino-3-phenylpropyl,

amino,

(C₁ -C₄)-alkoxycarbonylamino,

benzyloxycarbonylamino,

1-deoxyhexoketosyl or 1-deoxypentoketosyl, such as

1-deoxyfructos-1-yl, 1-deoxysorbos-1-yl or

1-deoxyribulos-1-yl,

hexosyl or pentosyl, such as

mannosyl, glucosyl or galactosyl, or

xylosyl, ribosyl or arabinosyl, where the linked sugars can be presentin the pyranose or the furanose form,

R² and R² *, independently of each other, are

hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl,sec-butyl, pentyl or hexyl,

cyclopentylmethyl or cyclohexylmethyl,

4-methylcyclohexylmethyl,

phenyl,

benzyl,

2-phenylethyl,

1-naphthylmethyl or 2-naphthylmethyl,

2-methylbenzyl, 3-methylbenzyl or 4-methylbenzyl,

2,4,6-trimethylbenzyl,

4-tert-butylbenzyl,

4-methoxybenzyl,

3,4-dihydroxybenzyl,

3,4-dimethoxybenzyl,

2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, or

2-(4-pyridyl)ethyl,

R³, R³ *, R⁴, R⁴ *, R¹⁰ and R¹⁰ * are hydrogen;

R⁵ and R⁶ are defined as described under c1.5);

R⁸ and R⁸ *, independently of each other, are

hydrogen or

form, together with R⁹ or R⁹ *, respectively, and the atoms carrying thelatter, a 1,2,3,4-tetrahydroisoquinoline or 2-azabicyclooctane skeleton;

R⁹ and R⁹ *,

independently of each other, are defined as are R⁹ and R⁹ *,respectively, under c1.5);

R¹¹ and R¹¹ *, independently of each other, are

hydrogen,

hydroxyl or

acetoxy;

where,

in the above compounds of this invention, one or more amide groups(--CONH--) of the main chain can be replaced by --CH₂ NH-- or--CH(OH)CH₂ --;

and the physiologically tolerated salts thereof.

Compounds of the formula I are furthermore paticularly preferred inwhich c1.7),

the radicals and symbols with and without an asterisk are in each caseidentical,

Q is a radical of the formula IIa,

Y is oxygen,

A is a radical of the formula IV in which

E, F or G are Gly, Ala, Val, Leu, Ile, Nva, Nle, Phe, Tyr, Asp or Glu,and

n+o+p is 0 or 1,

D is R¹ or a radical of the formulae V or VI,

R¹ is hydrogen, (C₁ -C₆)-alkylsulfonyl, (C₆ -C₁₀)-aryl-(C₁ -C₂)-alkyl,triphenylmethyl, (C₁ -C₆)-alkoxycarbonyl, (C₆ -C₁₀)-aryl-(C₁-C₂)-alkanoyl, (C₆ -C₁₀)-aryloxy-(C_(1-C) ₂)-alkanoyl, Het-carbonyl or(C₆ -C₁₀)-aryl-(C₁ -C₂)-alkoxycarbonyl,

R² is hydrogen, phenyl, benzyl, methyl, ethyl, isopropyl, n-propyl,n-butyl, isobutyl, sec-butyl, pentyl or cyclohexylmethyl,

R³, R⁴, R⁸, R¹⁰ and R¹¹ are hydrogen,

R⁵ is hydrogen or (C₁ -C₆)-alkyl,

R⁶ is oxygen, and

R⁹ is hydrogen, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,benzyl, carboxymethyl, carboxyethyl, 1-naphthylmethyl, 2-naphthylmethyl,2-(methylthio)ethyl, 2-(methylsulfinyl)ethyl, 2-(methylsulfonyl)ethyl,indol-2-ylmethyl or indol-3-ylmethyl,

and the physiologically tolerated salts thereof.

Compounds of the formula I, c1.8), may likewise be particularlypreferably mentioned in which the radicals and symbols with and withoutan asterisk are in each case identical,

Q is a radical of the formula IIa,

Y is oxygen;

A is a radical of the formula IV, where

E, F or G is Val, Phe, Ile or Asp, and

n+o+p is 0 or 1;

D is R¹ or a radical of the formulae V or VI;

R¹ is hydrogen, (C₁ -C₆)-alkylsulfonyl, phenyl-(C₁ -C₂)-alkyl,triphenylmethyl, (C₁ -C₆)-alkoxycarbonyl or phenyl-(C₁-C₂)-alkoxycarbonyl,

R² is hydrogen, phenyl, benzyl, methyl, ethyl, isopropyl, n-propyl,n-butyl, isobutyl, sec-butyl, pentyl or cyclohexylmethyl,

R³, R⁴, R⁸, R¹⁰ and R¹¹ are hydrogen,

R⁵ is hydrogen or (C₁ -C₄)-alkyl,

R⁶ is oxygen, and

R⁹ is hydrogen, isopropyl, sec-butyl, benzyl, carboxymethyl,1-naphthylmethyl, 2-(methylthio)-ethyl or indol-2-ylmethyl,

and the physiologically tolerated salts thereof.

The present invention furthermore relates to a process for preparingcompounds of the formula I, wherein a fragment having a terminalcarboxyl group, or a reactive derivative of this fragment, is coupled toa corresponding fragment having a free amino group, (a) protectivegroup(s) which has/have, where appropriate, been temporarily introducedto protect further functional groups is/are eliminated, and the compoundthus obtained is, where appropriate, converted into its physiologicallytolerated salt.

Fragments of a compound of the formula I having a terminal carboxylgroup possess the following formulae, for example:

    ______________________________________                                               D - OH           (VIII)                                                       D - E - OH       (IX)                                                         D - F - OH       (x)                                                          D - G - OH       (XI)                                                         D - E - F - OH   (XII)                                                        D - E - G - OH   (XIII)                                                       D - F - G - OH   (XIV)                                                        D - E - F - G - OH                                                                             (XIVa)                                                ______________________________________                                    

The same is correspondingly true for the analogous radicals marked withan asterisk.

Fragments of a compound of the formula I having a terminal amino grouppossess the following formulae, for example:

    H--Z--H                                                    (XV)

    H--G--Z--G*--H                                             (XVI)

    H--F--Z--F*--H                                             (XVIa)

    H--E--Z--E*--H                                             (XVIb)

    H--F--G--Z--G*--F*--H

    H--E--G--Z--G*--E*--H                                      (XVIIa)

    H--E--F--Z--F*--E*--H                                      (XVIIb)

    H--E--F--G--Z--G*--F*--E*--H                               (XVIII)

where Z is a radical of the formula (XIX): ##STR6## In the event thatthe two radicals bonded to Q are different, other fragments besidesthose of the formulae XV to XVIII, which may possibly be protected at aterminal amino group, can also be employed.

Methods which are suitable for preparing an amide bond are described,for example, in Houben-Weyl, Methoden der organischen Chemie [Methods oforganic chemistry], Volume 15/2; Bodansky et al., Peptide Synthesis. 2nded. (Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides:Analysis, synthesis, biology (Academic Press, New York 1979). Use ispreferably made of the following methods: active ester method usingN-hydroxysuccinimide, 1-hydroxybenzotriazole or3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine as the alcoholcomponent, coupling with a carbodiimide such as dicyclohexylcarbodiimide(DCC) or with n-propanephosphonic anhydride (PPA) and the mixedanhydride method using pyvaloyl chloride or ethyl chloroformate orisobutyl chloroformate, or coupling with phosphonium reagents such asbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP) or uronium reagents such as2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU).

Fragments of the formula (VIII) or (VIII*) are synthesized, providedthey

a) fall within formula (V) or (V*), in accordance with the generalmethods for preparing amino acids;

b) fall within formula (VI) or (VI*), proceeding, for example, from thecorresponding amino acids, with the centers of chirality of these aminoacids being retained. Diazotization at from -20° C. to 50° C. in dilutemineral acids gives rise to α-bromocarboxylic acids or, via the lacticacids, to α-trifluoromethanesulfonyloxycarboxylic acids which can bereacted with a nucleophile carrying R¹ and R¹¹ or R¹ * and R¹¹ *,respectively, or are prepared, for example, proceeding from malonicesters whose alkylation yields mono-substituted or di-substitutedmalonic esters which, following hydrolysis, are converted by means ofdecarboxylation into the desired derivatives;

c) fall within formula (VII) or (VII*), proceeding from thecorresponding α-amino acids, with the centers of chirality of theseamino acids being retained. Diazotization at from -20° C. to 50° C. indilute mineral acids gives rise to lactic acids which can be reactedwith an electrophile carrying a R¹ or R¹ *.

Fragments of the formulae (IX), (X), (XI), (XII) and (XIII), (XIV) and(XIVa) are synthesized in accordance with the general, known methods forpreparing amino acids and peptides.

Fragments of the formula XV are synthesized in accordance with knownprocesses (K. Sasse in Houben-Weyl, Methoden der organischen Chemie[Methods of organic chemistry], Volume 12/1, Georg Thieme Verlag,Stuttgart, 1963; U. H. Felcht in Houben-Weyl, Methoden der organischenChemie [Methods of organic chemistry], Volume 12/E/2, Georg ThiemeVerlag, Stuttgart, 1982; D. Redmore in Griffiths, Ed., PhosphorusChemistry, vol. 8, p. 515). Use is preferably made of the followingmethods:

1) Synthesis of the Compounds of the Formula XVa

    B Z B                                                      (XVa)

where B is protective groups, in particular benzyloxycarbonyl, byreacting substituted α-aminophosphonites, which are prepared by knownmethods (J. Org. Chem. 53 (1988) 4500), e.g. ethyl1-benzyloxycarbonylamino-2-phenylethylphosphonite, with substitutedα-aminoaldehydes, which are prepared by known methods, e.g.N-benzyloxycarbonylamino-L-phenylalaninal (Lit. Tetrahedron Lett 22(1988) 3815; ibid 31 (1990) 7359).

The reactions are carried out in an organic solvent, preferablychloroform, by means of base catalysis, preferably using triethylamineat from -78° C. to 100° C., preferably at approximately 60° C.

Peptide analogs of this nature can be prepared by known methods whichcan be found, for example, in the following references:

A. F. Spatola in "Chemistry and Biochemistry of Amino Acids Peptides andProteins" 1983 (B. Weinstein et al. eds.) Marcel Dekker, New York, p.267 (Review article);

J. S. Morley, Trends Pharm Sci. (1980), pp. 463-468 (Review article); D.Hudson et al., Int. J. Pept. Prot. Res. (1979), 14, 177-185 (--CH₂ NH--,--CH₂ CH₂ --);

A. F. Spatola et al., Life Sci. (1986), 38, 1243-1249 (--CH₂ --S--);

M. M. Hann, J. Chem. Soc. Perkin Trans. I (1982) 307-314 (--CH═CH-- cisand trans);

J. K. Whitesell et al., Chirality 1, (1989) 89-91 (--CH═CH-- trans)

R. G. Almquist et al., J. Med. Chem. (1980), 23, 1392-1398 (--COCH₂ --);

C. Jennings-White et al., Tetrahedron Lett. (1982) 23, 2533 (--COCH₂--);

M. Szelke et al., EP-A 45665 (1982), CA: 97: 39405 (--CH(OH)CH₂ --);

M. W. Holladay et al., Tetrahedron Lett. (1983) 24, 4401-4404(--CH(OH)CH₂ --);

V. J. Hruby, Life Sci. (1982), 31, 189-199 (--CH₂ --S--);

N. E. Jacobsen, P. A. Barlett, J. Am. Chem. Soc. (1981) 103, 654-657(--P(O)(OR)NH--).

The preliminary operations and final operations which have to be carriedout in association with preparing compounds of the formula I, such asthe introduction and elimination of protective groups, are known fromthe literature and are described, for example, in T. W. Greene"Protective Groups in Organic Synthesis" (John Wiley & Sons, New York,1981). Salts of compounds of the formula I having salt-forming groupsare prepared, in a manner known per se, by, for example, reacting acompound of the formula I having a basic group with a stoichiometricquantity of a suitable acid or reacting compounds of the formula Ihaving an acid group with a stoichiometric quantity of a suitable base.Stereoisomeric mixtures, in particular diastereomeric mixtures, whichmay result in association with the synthesis of compounds of the formulaI can be resolved, in a manner known per se, by fractionalcrystallization or by chromatography.

The compounds of the formula I according to the invention exhibitenzyme-inhibiting properties. In particular, they inhibit HIV protease.Their enzyme-inhibitory effect, which is in the milli- to subnano-molarrange, can be determined as follows.

Test Principle

The substrates of the HIV protease which have been employed thus farinclude the heptapeptide: H-Ser-Phe-Asn-Phe-Pro-Gln-Ile-OH (SEQ IDNO. 1) (P. L. Darke et al., Biophys. Res. Commun. 156 (1988) 297-303).When this peptide is used as the substrate, the HIV protease cleaves itbetween the second Phe and the Pro.

It has now been found, surprisingly, that substituting 5-oxaproline forproline in this sequence gives rise to a substrate which can be cleavedconsiderably faster by the HIV protease and thus permits more rapidanalysis requiring smaller quantities of enzyme.

General instructions for testing inhibitors of the HIV proteases:

a) Preparation of the Substrate Solution

2 mg of H-Ser-Phe-Asn-Phe-Opr-Gln-Ile-OH (H-Opr-OH=5-oxaproline) (SEQ IDNO. 1) are dissolved in 1 ml of MGTE 15 buffer (use of ultrasonicationif required) and this solution is subsequently filtered through asterilizing filter (0.45 μm).

b) Preparation of the Inhibitor Solution

2.5 times the necessary quantity of inhibitor to give the desiredmolarity per ml of solution is weighed out and dissolved in DMSO (10% ofthe final volume). This solution is diluted with MGTE 15 buffer to thefinal volume and then filtered through a sterilizing filter (0.45 μm).

c) Preparation of the Protease Solution

5 μl of the HIV protease solution are diluted with MGTE25 buffer asrequired.

d) Implementation of the Test

In each case, 10 μl of the substrate solution are pipetted into a testtube (16×100) having a screw cap. 10 μl of MGTE 15 buffer, whichcontains 10% DMSO, are pipetted in for the blank experiment. 10 μl ofthe inihibitor solutions are added to each of the remaining test tubes.The tubes are incubated at 37° C. for 5-10 minutes and 5 μl of theprotease solution are then added to each sample. Following reaction at37° C. for 2 hours, 10 or 20 μl (depending on the sensitivity of theHPLC equipment) are pipetted out from each sample, added to microvialsand diluted with 120 μl of the HPLC eluant.

e) Conditions for the HPLC Analysis

Eluant system:

80% 0.1M phosphoric acid, pH 2.5

20% (w/w) acetonitrile

Column: Merck ®LICHROSORB RP18 (5 μm) 250×4

Rate of flow: 1 ml/min

Temperature of the column: 42° C.

Detector parameters: 215 nm, 0.08 AUF, 18.2° C.

Analysis time: 11 minutes

Retention time for the substrate: 8.1 minutes

Retention time for the N-terminal tetrapeptide: 3.9 minutes

f) Solvents Required

1) MGTE 15 buffer:

20 mM morpholinoethanesulfonic acid (MES)

15% (w/v) glycerol

0.1% (v/v) Triton×100

5 mM EDTA

0.5M NaCl

1 mM phenylmethylsulfonyl fluoride (PMSF)

2) MGTE 25 buffer:

Composition similar to that of MGTE 15 buffer with the followingdifferences:

25% (w/v) glycerol, and, in addition, 1 mM dithiothreitol (DTT)

MES, EDTA, NaCl, DTT and PMSF are weighed into a conical flask anddissolved in a little water, and this solution is adjusted to pH 6. Theappropriate quantity of glycerol is weighed into a volumetric flask and®Triton×100 is added to it by pipette. The aqueous solution istransferred into the volumetric flask, which is filled to the mark withwater.

3) HPLC Eluant

A 0.1M solution of ortho-phosphoric acid (FLUKA puriss. p.a.) isprepared. This solution is adjusted precisely to pH 2.5 usingtriethylamine (FLUKA puriss. p.a.). The weight of the solution isdetermined and the appropriate quantity of acetonitrile (fume cupboard!)is weighed into it. The constituents are mixed thoroughly and degassedfor about 5 minutes using helium 5.0.

g) Evaluation

Under the conditions chosen for this experiment, the heptapeptide isseparated from the N-terminal tetrapeptide resulting from the enzymiccleavage. The % content of tetrapeptide peak related to the sum oftetrapeptide+heptapeptide gives the cleavage rate. The following IC₅₀values indicate the inhibitor concentrations at which the cleavage rateis halved:

    ______________________________________                                                Example           IC.sub.50                                           ______________________________________                                                No.  3            70    nM                                                         4            1.3   nM                                                         7            15    nM                                                         8            0.5   nM                                                         10           4.2   nM                                            ______________________________________                                    

The target peptide was assembled step-wise using a model 430 A peptidesynthesizer from Applied Biosystems, and using the Fmoc method, on ap-benzyloxybenzylalcohol resin, which was esterified with Fmoc-Ile-OH,from Novabiochem (loading, approximately 0.5 mmol/h of resin). 1 g ofthe resin was employed and the synthesis was carried out using asynthesis program which was modified for the Fmoc method.

The following amino acid derivatives are used: Fmoc-Gln-OH, Fmoc-Opr-OH,Fmoc-Phe-OObt, Fmoc-Asn-OH and Fmoc-Ser(tBu)-OObt. In order tosynthesize FmocOpr-OH, H-Opr-OtBu was synthesized by the method ofVasella et al. (J. C. S. Chem. Comm. 1981, 97-98) and, reacted withFmoc-OSu in 15 dioxane/water (1:1) in the presence of NaHCO₃. Subsequentcleavage of the tert-butyl ester with trifluoroacetic acid yieldsFmoc-Opr-OH.

1 mmol of the amino acid derivatives having a free carboxyl group was ineach case weighed into the cartridges of the synthesizer together with0.95 mmol of HOObt. These amino acids were pre-activated directly in thecartridges by dissolving them in 4 ml of DMF and adding 2 ml of a 0.55molar solution of diisopropylcarbodiimide in DMF. The HOObt esters ofthe other amino acids were dissolved in 6 ml of NMP and then, like thein-situ pre-activated amino acids, coupled to the resin, which hadpreviously been unblocked using 20% piperidine in DMF. Once thesynthesis was complete, the peptide was cleaved off from the resin, withthe side-chain protective groups being simultaneously removed, withtrifluoroacetic acid using thioanisole and ethanedithiol ascation-capturing agents. The residue obtained after stripping off thetrifluoroacetic acid was digested several times with ethyl acetate andcentrifuged.

The remaining residue was chromatographed on an alkylated dextran gelusing 10% acetic acid. The fraction containing the pure peptide wascombined and freeze-dried.

Mass spectrum (FAB): 854 (M+H+) Amino acid analysis: Asp: 0.98; Ser:0.80; Glu: 1.00; Ile: 1.05; Phe: 2.10; NH₃ : 1.76.

The invention also relates to the use of the compounds of the formula Ias medicines and pharmaceutical preparations which contain thiscompound. Their use in primates, in particular in humans, is preferred.

Pharmaceutical preparations contain an effective quantity of the activecompound of the formula I together with an inorganic or organicpharmaceutically utilizable carrier substance. Administration can beeffected intranasally, intravenously, subcutaneously or perorally. Thedosage which is to be used of the active compound depends on thehomeothermic species, the bodyweight, the age and the route ofadministration.

The pharmaceutical preparations of the present invention are produced bydissolution processes, mixing processes, granulating processes orcoating processes which are known per se.

For an oral application form, the active compounds are mixed with theadditives which are customary for this purpose, such as carriersubstances, stabilizers or inert diluents, and brought, by customarymethods, into suitable forms for administration, such as tablets, coatedtablets, hard gelatine capsules, aqueous, alcoholic or oily suspensions,or aqueous, alcoholic or oily solutions. Gum arabic, magnesium oxide,magnesium carbonate, potassium phosphate, lactose, glucose, magnesiumstearylfumarate or starch, in particular corn starch, can, for example,be used as inert excipients. In this context, the preparation can beeffected as a dry granulate or as a wet granulate. Vegetable or animaloils, such as sunflower oil and cod-liver oil, are, for example,suitable for use as oily carrier substances or solvents.

For subcutaneous or intravenous administration, the active compounds, ortheir physiologically tolerated salts, are brought into solution,suspensions or emulsions, if desired together with the substances whichare customary for this purpose, such as solubilizers, emulsifiers orother auxiliary substances. Examples of suitable solvents are: water,physiological solutions of sodium chloride, or alchohols, e.g. ethanol,propanediol or glycerol, and also sugar solutions, such as solutions ofglucose or mannitol, or else a mixture of the different solvents whichhave been mentioned.

It is also possible to use injectable control-release preparations.Examples of pharmaceutical forms which can be used are oily crystalsuspensions, microcapsules, rods or implants, it being possible for thelatter to be made of tissue-compatible polymers, in particularbiodegradable polymers, such as, for example, those based on polylacticacid/polyglycolic acid copolymers, or human albumin.

List of Abbreviations

Boc tert-butyloxycarbonyl

Chg cyclohexylglycl

d doublet

TLC thin layer chromatography

DCC dicyclohexylcarbodiimide

DCM dichloromethane

DMF dimethylformamide

DMAP 4-dimethylaminopyridine

DMSO dimethyl sulfoxide

EDAC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EA ethyl acetate

FAB fast atom bombardment

HOBt hydroxybenzotriazole

i. V. in vacuo

m multiplet

M molecular peak

NEM N-ethylmorpholine

Npg neopentylglycyl

MS mass spectrum

PPA n-propylphosphonic anhydride

RT room temperature

s singlet

m.p. melting point

t triplet

Tbg tert-butylglycyl

TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate

THF tetrahydrofuran

Thia 2-thienylalanyl

Z benzyloxycarbonyl

The other abbreviations used for amino acids conform to the three-lettercode which is customary in peptide chemistry (as described, for example,in Eur. J. Biochem. 138, (1984), 9-37). Unless expressely indicatedotherwise, an amino acid is always in the L configuration.

The following examples serve to illustrate the present invention withoutrestricting it thereto.

EXAMPLE 1 a) 1-Diphenylmethylamino-2-phenylethylphosphonous acid

A solution of 17.59 g (0.124 mol) of phenyl acetaldehyde in 20 ml ofdioxane is slowly added dropwise to a suspension, which is heated at100° C. under argon, of 31.85 g (0.124 mol) ofdiphenylmethylaminohypophosphite in 350 ml of dioxane, prepared bymixing equimolar quantities of diphenylmethylamine and hypophosphorousacid (100%) in ethanol. The reaction solution is stirred at thistemperature for 1 h. The water of reaction which has formed is removedby azeotropic distillation using 280 ml of dioxane. Once the reactionsolution has been cooled down and diluted with 150 ml of ethanol, theproduct, which slowly precipitates out, is filtered off with suction,washed with ethanol/diethyl ether and dried over P₂ O₅. Yield: 9.84 g(22.5%); m.p.: 209°-211° C.; MS: 352 (M+H)⁺ ; 286; 167.

b) 1-Amino-2-phenylethylphosphonous acid

9.9 g (0.028 mol) of 1-diphenylmethylamino-2-phenylethylphosphonous acidare heated, at 100°-105° C. for 2 h, in 50 ml of 40% hydrobromic acid.The reaction solution is then evaporated to dryness i.V. and the residueis taken up in 50 ml of water. The aqueous solution is washed severaltimes with diethyl ether and evaporated to dryness. The residue isdissolved in 60 ml of ethanol and propylene oxide is added to thesolution until the product precipitates out. After the mixture has beenleft to stand overnight, the precipitate is filtered off with suction,washed with ethanol/diethyl ether and dried.

Yield: 4.23 g (82%); m.p.: 225°-226° C.; MS: 186 (M+H)⁺ ; 120

c) 1-Benzyloxycarbonylamino-2-phenylethylphosphonous acid

2.25 ml (14.25 mmol) of benzyl chloroformate are added dropwise, at 0°C. and within the space of 30 min., to a suspension of 1.76 g (9.5 mmol)of 1-amino-2-phenylethylphosponous acid in 15 ml of 1M NaOH, 5 ml ofwater and 5 ml of dioxane. During a further 2.5 h of stirring at 0° C.,the pH of the mixture is maintained at 9-10 using 1M NaOH (approximately10 ml). After removing the cooling medium, the mixture is stirred at RTovernight. The reaction solution is then washed several times withdiethyl ether. The aqueous phase is adjusted to pH 2, at 0°-5° C., using6M HCl and extracted several times with ethyl acetate. The combinedextracts are washed with a saturated solution of NaCl, dried with Na₂SO₄, filtered and subjected to rotary evaporation i.V. A solid residueremains which is recrystallized from ether/petroleum ether.

Yield: 2.62 g (86%); MS: 342 (M+Na)⁺, 320 (M+H)⁺ ; 254 m.p.: 136°-137°C.

d) Ethyl 1-benzyloxycarbonylamino-2-phenylethylphosphonite

2.24 ml (25 mmol) of pyridine are added dropwise, at RT and within thespace of 20 min., to a suspension of 7.98 g (25 mmol) of1-benzyloxycarbonylamino-2-phenylethylphosphonous acid and 2.53 ml (25mmol) of ethyl chloroformate under argon in 200 ml of chloroform. Thereaction solution is stirred for a further 30 min. at this temperature.It is then heated at 70° C. for 1 h. After the solvent has beenevaporated off i.V., the residue is taken up in ethyl acetate, washedwith water and a saturated solution of NaCl, dried over Na₂ SO₄,filtered and evaporated i.V. The solid residue which remains isrecrystallized from ether/petroleum ether.

Yield: 7.6 g (88%); MS: 348 (M+H)⁺ ; 254; 210

e) 2-Benzyloxycarbonyl-L-phenylalanine-N-methoxy-N-methylamide

31.8 ml (0.18 mol) of N-ethyldiisopropylamine are added dropwise, at 0°C., to a solution of 17.94 g (0.06 mol) ofbenzyloxycarbonylphenylalanine, 5.97 g (0.06 mol) ofN,O-dimethylhydroxylamine hydrochloride, 8.79 g (0.06 mol) of ethylhydroxyiminocyanoacetate and 19.68 g (0.06 mol) of TOTU in 120 ml ofDMF. The mixture is stirred at 0° C. for 1 h and at RT for 3 h. Thesolvent is removed by rotary evaporation i.V. and the residue is takenup in ethyl acetate; the solution thus obtained is washed several timeswith a 10% solution of citric acid, with a 10% solution of KHCO₃ andwith a saturated solution of NaCl. Once the solution has been dried overNa₂ SO₄ and filtered, and the filtrate has been concentrated, 13.95 g(68%) of an oil remain.

MS: 343 (M+H)⁺

f) N-Benzyloxycarbonyl-L-phenylalaninal

4.35 g (12.71 mmol) of2-benzyloxycarbonyl-L-phenylalanine-N-methoxy-N-methylamide, dissolvedin 40 ml of diethyl ether, are added dropwise, within the space of 30min., to a suspension, which is stirred at 0° C. under argon, of 0.965 g(25.42 mmol) of lithium aluminum hydride in 140 ml of diethyl ether.After a further 30 min., the cooling medium is removed and the mixtureis stirred at RT for 30 min. 50 ml of ice water are then added carefullyto it and this mixture is filtered. The filtrate is adjusted to pH 4using 10% H₂ SO₄ and extracted several times with ether. The combinedether extracts are washed with water and a saturated solution of NaCl,dried over Na₂ SO₄, filtered and freed from solvent i.V.

The oily product remains.

Yield: 3.41 g (95%); MS: 284 (M+H)⁺ ; 254; 240; 210

g) Ethyl1-(2-benzyloxycarbonylamino-1-hydroxy-3-phenylpropyl),1-(1-benzyloxycarbonylamino-2-phenylethyl)phosphinate

A solution of 4.18 g (12 mmol) of ethyl1-benzyloxycarbonylamino-2-phenylethylphosphonite, 3.41 g (12 mmol) ofN-benzyloxycarbonyl-L-phenylalaninal and 0.85 ml (6 mmol) oftriethylamine in 100 ml of chloroform is stirred, under argon, at RT for20 h. A further 0.85 ml (6 mmol) of triethylamine is then added. Themixture is boiled at reflux for 9 h. Once the solvent has been removedby rotary evaporation, the residue is dissolved in 200 ml of ethylacetate and this solution is washed several times with water and asaturated solution of NaCl. The org. phase is dried with Na₂ SO₄,filtered and subjected to rotary evaporation i.V. The residue ispurified by chromatography on silica gel (ethyl acetate/n-heptane: 5/1).

Yield: Isomer A, 1.74 g (23%); isomer B, 0.81 g (11%) MS: 631 (M+H) ⁺ ;240; 210

EXAMPLE 2 Ethyl1-(2-amino-1-hydroxy-3-phenylpropyl),1-(1-amino-2-phenylethyl)phosphinatedihydrochloride

1.5 g (2.38 mmol) of ethyl1-(2-benzyloxycarbonylamino-1-hydroxy-3-phenylpropyl),1-(1-benzyloxycarbonylamino-2-phenylethyl)phosphinate(isomer A) are dissolved in 80 ml of methanol and hydrogenated with H₂for 3 h using 0.3 g of Pd/C (10%), during which process the pH of thereaction solution is maintained at 3 using methanolic HCl. The catalystis filtered off and the filtrate is evaporated to dryness. The remainingproduct is recrystallized from isopropanol/ether.

Yield: 0.9 g (87%); MS: 363 (M+H)⁺ ; 244; 120

EXAMPLE 3 Ethyl1-{2-[(benzyloxycarbonyl-L-valyl)amino]-1-hydroxy-3-phenylpropyl},1-{1-[(benzyloxycarbonyl-L-valyl)amino]}-2-phenylethyl}phosphinate

[lacuna] are [lacuna], at 0° C., to a solution of 440 mg (1 mmol) of thecompound from Example 2, 306 mg (2.5 mmol) of benzyloxycarbonylvalene,360 mg (2.5 mmol) of ethyl hydroxyiminocyanoacetate and 820 mg (2.5mmol) of TOTU in 40 ml of DMF and [lacuna] is stirred at RT for 4 h. Thesolvent is removed by rotary evaporation i.V. and the residue isdissolved in 100 ml of ethyl acetate. The ethyl acetate solution iswashed several times with a 10% solution of citric acid, with a 10%solution of KHCO₃ and with a saturated solution of NaCl, dried over Na₂SO₄, filtered and evaporated to dryness i.V. The solid residue isrecrystallized from ethyl acetate.

Yield: 0.58 g (70%); MS: 851 (M+Na)⁺, 829 (M+H)⁺

EXAMPLE 41-{2-[(Benzyloxycarbonyl-L-valyl)amino]-1-hydroxy-3-phenylpropyl},1-{-[(benzyloxycarbonyl-L-valyl)amino]-2-phenylethyl}phosphinicacid

0.06 ml (0.447 mmol) of trimethylsilyl bromide is added dropwise at 0°C., to a solution, under argon, of 124 mg (0.149 mmol) of the compoundfrom Example 3 in 5 ml of tetrahydrofuran. After 1 h at this temperatureand 24 h at RT, 2 ml of ice water are added to the solution and thismixture is extracted with 50 ml of ethyl acetate, filtered andevaporated i.V. A viscous oily product remains. Purification is effectedby chromatography on silica gel (ethyl acetate/n-heptane: 5/1).

Yield: 25.6 mg (21.5%); MS: 823 (M+Na)⁺ ; 801 (M+H)⁺

EXAMPLE 5 Ethyl1-[2-(L-valylamino)-1-hydroxy-3-phenylpropyl],1-[L-valylamino)-2-phenylethyl]phosphinatedihydrochloride

Synthesized, in analogy with Example 2, from ethyl1-{2-[(benzyloxycarbonyl-L-valyl)amino]-1-hydroxy-3-phenylpropyl},1-{1-[(benzyloxycarbonyl-L-valyl)amino]-2-phenylethyl}phosphinate.

Yield: 0.24 g (90%); MS: 561 (M+H)⁺ ; 462; 249

EXAMPLE 6 Ethyl1-{2-[(N-tert-butyloxycarbonyl-L-naphthylalanyl-L-valyl)amino]-1-hydroxy-3-phenylpropyl},1-{1-[(N-tert-butyloxycarbonyl-L-naphthylalanyl-L-valyl)amino]-2-phenylethyl}phosphinate

340 mg (1.64 mmol) of 1,1'-carbonyldiimidazole are added, at 0° C., to asolution of 470 mg (1.5 mmol) ofN-tert-butyloxycarbonyl-L-naphthylalanine and 202 mg (1.5 mmol) of1-hydroxybenzotriazole in 15 ml of tetrahydrofuran. The mixture isstirred at 0° C. for 15 min. and at RT for 2 h. The active estersolution thus obtained is added, also at 0° C., to a mixture comprising320 mg (0.5 mmol) of the compound from Example 5 and 0.17 ml (1 mmol) ofN-ethyldiisopropylamine in 15 ml of DMF, and this is followed by afurther 0.34 ml (2 mmol) of N-ethyldiisopropylamine. The reactionmixture is then stirred at 0° C. for 2 h and at RT for 4 h. The solventis removed by rotary evaporation i.V. and the residue is purified bychromatography on silica gel (CH₂ Cl₂ /CH₃ OH: 40/1).

Yield: 360 mg (62%); MS: 1178 (M+Na)⁺, 1156 (M+H)⁺

EXAMPLE 7 Ethyl1-{2-[(L-naphthylalanyl-L-valyl)amino]-1-hydroxy-3-phenylpropyl},1-{1-[(L-naphthylalanyl-L-valyl)amino]-2-phenylethyl}phosphinatebistrifluoroacetate

A solution of 72 mg (0.06 mmol) of the compound obtained from Example 6in 2 ml of trifluoroacetic acid is stirred at RT for 1 h and thenevaporated to dryness i.V. The product precipitated by adding ethylacetate is filtered off with suction, washed with ether and dried overP₂ O₅.

Yield: 56.7 mg (80%); MS: 997.5 (M+Na)⁺, 955.5 (M+H)⁺

EXAMPLE 81-{2-[(L-Naphthylalanyl-L-valyl)amino]-1-hydroxy-3-phenylpropyl},1-{1-[(L-naphthylalanyl-L-valyl)amino]-2-phenylethyl}phosphinicacid dihydrobromide

543 mg (0.47 mmol) of the compound obtained from Example 7 are treatedwith 0.5 ml (3.81 mmol) of trimethylsilyl bromide in analogy with themethod described in Example 4. The crude product is purified bychromatography on silica gel (CH₂ Cl₂ /CH₃ OH: 5/1).

Yield: 255 mg (50%); MS: 965.8 (M+K)⁺ ; 927.4 (M+H)⁺

EXAMPLE 9 Ethyl1-{2-[((2S(tert-butylsulfonylmethyl)-3-(1-naphthyl)-propionyl)-L-valyl)amino]-1-hydroxy-3-phenylpropyl},1-{1-[((2S(tert-butyl-sulfonylmethyl)-3-(1-naphthyl)propionyl)-L-valyl)amino]-2-phenylethyl}phosphinate

321 mg (1.56 mmol) of N,N'-dicyclohexylcarbodiimide are added, at 0° C.,to a solution of 521 mg (1.56 mmol) of2S(tert-butylsulfonylmethyl)-3-(1-naphthyl)propionic acid and 254 mg(1.56 mmol) of 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine in 3 mlof tetrahydrofuran. The mixture is stirred at 0° C. for 30 min. and atroom temperature for 20 min. After filtration, the resulting activeester solution is added, at 0° C., to a mixture comprising 330 mg (0.52mmol) of the compound from Example 5 and 0.18 ml (1.04 mmol) ofN-ethyldiisopropylamine in 30 ml of DMF, and this is followed by afurther 0.36 ml (2.08 mmol) of N-ethyldiisopropylamine. The reactionmixture is then stirred at 0° C. for 2 h and at room temperature for 24h. The solvent is removed by rotary evaporation i.V. and the residue istaken up in 150 ml of ethyl acetate. The ethyl acetate solution iswashed several times with a 10% solution of citric acid, with a 10%solution of KHCO₃ and with a saturated solution of NaCl, dried oversodium sulfate, filtered and evaporated to dryness i.V. Purification iseffected by chromatography on silica gel (ethyl acetate/n-heptane: 5/1).

Yield: Isomer A, 0.21 g (34%) Isomer B, 0.15 g (24%) MS: 1215 (M+Na)⁺ ;1193 (M+H)⁺

EXAMPLE 101-{2-[((2S(tert-Butylsulfonylmethyl)-3-(1-naphthyl)-propionyl)-L-valyl)amino]-1-hydroxy-3-phenylpropyl},1-{1-[((2S(tert-butylsulfonylmethyl)-3-(1-naphthyl)propionyl)-L-valyl)amino]-2-phenylethyl}phosphinicacid

180 mg of isomer A and 120 mg of isomer B from Example 9 are treatedwith trimethylsilyl bromide in analogy with the method described inExample 7. The crude products are purified by chromatography on silicagel (CH₂ Cl₂ /CH₃ OH: 5/1).

Yield: 88 mg (50%) of isomer A 55 mg (47%) of isomer B MS: 1209(M+2Na--H)⁺ ; 1203 (M+K)⁺ ; 1187 (M+Na)⁺

    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 2                                                  (2) INFORMATION FOR SEQ ID NO:1:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                       SerPheAsnPheProGlnIle                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:2:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 5                                                               (D) OTHER INFORMATION: /note= "Xaa = 5 oxaproline."                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                       SerPheAsnPheXaaGlnIle                                                         15                                                                            __________________________________________________________________________

We claim:
 1. A compound of the formula I ##STR7## in which Q is aradical of the formula IIa or IIb ##STR8## Y is oxygen or sulfur, and Ais a radical of the formula IV and A* is a radical of the formula IV*,

    D--(E)n--F(o)--(G)p--                                      (IV)

    D*--(E*)n*--(F*)o*--(G*)p*                                 (IV*)

where E, E*, F, F*, G and G*, independently of each other, are a naturalor unnatural amino acid, azaamino acid or imino acid; n, n*, o, o*, pand p*, independently of each other, are 0 or 1; D is R¹ or a radical ofthe formulae V, VI or VII, and D* is R¹ * or a radical of the formulaeV*, VI* or VII*, ##STR9## and in which R¹ and R¹ *, independently ofeach other, a1) are hydrogen, carboxyl, (C₁ -C₁₈)-alkyl, which isoptionally unsaturated once or twice and which is optionally substitutedby up to 3 identical or different radicals from the groupmercapto,hydroxyl, (C₁ -C₇)-alkoxy, carbamoyl, (C₁ -C₈)-alkanoyloxy, carboxyl,(C₁ -C₇)-alkoxycarbonyl, F, Cl, Br, I, amino, amidino, which can beoptionally substituted by one, two or three (C₁ -C₈)-alkyl radicals,guanidino, which can be optionally substituted by one or twobenzyloxycarbonyl radicals or by one, two, three or four (C₁ -C₈)-alkylradicals, (C₁ -C₇)-alkylamino, di-(C₁ -C₇)-alkylamino, (C₁-C₆)-alkoxycarbonylamino, (C₇ -C₁₅)-aralkoxycarbonyl, (C₇-C₁₅)-aralkoxycarbonylamino, phenyl-(C₁ -C₄)-alkoxy,9-fluorenylmethoxycarbonylamino, (C₁ -C₆)-alkylsulfonyl, (C₁-C₆)-alkylsulfinyl, (C₁ -C₆)-alkylthio, hydroxyamino, hydroxyimino,sulfamoyl, sulfo, carboxamido, formyl, hydrazono, imino, phenyl, aradical CONR¹² R¹³ or CONR¹² *R¹³ *, by up to six hydroxyl, or by up tofive (C₁ -C₈)-alkanoyloxy; monocyclic, bicyclic or tricyclic (C₃-C₁₈)-cycloalkyl, (C₃ -C₁₈)-cycloalkyl-(C₁ -C₆)-alkyl where thecycloalkyl moiety is in each case optionally substituted by one or twoidentical or different radicals from the group F, Cl, Br, I, carboxyl,carbamoyl, carboxymethoxy, hydroxyl, (C₁ -C₇)-alkoxy, (C₁ -C₇)-alkyl,(C₁ -C₇)-alkyloxycarbonyl, amino, (C₁ -C₆)-alkylamino-(C₁ -C₆)-alkyl,di-(C₁ -C₆)-alkylamino-(C₁ -C₆)-alkyl, amidino, hydroxyamino,hydroxyimino, hydrazono, imino, guanidino, (C₁ -C₆)-alkoxysulfonyl, (C₁-C₆)-alkoxysulfinyl, (C₁ -C₆)-alkoxycarbonylamino, (C₆ -C₁₂)-aryl-(C₁-C₄)-alkoxycarbonylamino, (C₁ -C₇)-alkylamino, di-(C₁ -C₇)-alkylamino,and trifluoromethyl; (C₆ -C₁₄)-aryloxy-(C₁ -C₆)-alkyl, (C₆ -C₁₄)-aryl,(C₆ -C₁₄)-aryl-(C₁ -C₆)-alkyl, or (C₆ -C₁₄)-aryl-(C₃ -C₈)-cycloalkyl, inwhich the aryl moiety is in each case optionally substituted by one, twoor three identical or different radicals from the group F, Cl, Br, I,hydroxyl, mono-, di- or trihydroxy-(C₁ -C₄)-alkyl, trifluoromethyl,formyl, carboxamido, mono- or di-(C₁ -C₄)-alkylaminocarbonyl, nitro, (C₁-C₇)-alkoxy, (C₁ -C₇)-alkyl, (C₁ -C₇)-alkoxycarbonyl, amino, (C₁-C₇)-alkylamino, di-(C₁ -C₇)-alkylamino, carboxyl, carboxymethoxy,amino-(C₁ -C₇)-alkyl, (C₁ -C₇)-alkylamino-(C₁ -C₇)-alkyl, di-(C₁-C₇)-alkylamino-(C₁ -C₇)-alkyl, (C₁ -C₇)-alkoxycarbonylmethoxy,carbamoyl, sulfamoyl, (C₁ -C₇)-alkoxysulfonyl, (C₁ -C₈)-alkylsulfonyl,sulfo-(C₁ -C₈)-alkyl, guanidino-(C₁ -C₈)-alkyl and (C₁-C₆)-alkoxycarbonylamino; Het, Het-(C₁ -C₆)-alkyl, Het-(C₃-C₈)-cycloalkyl, Het-(C₃ -C₈)-cycloalkyl-(C₁ -C₄)-alkyl, Het-(C₃-C₈)-cycloalkoxy-(C₁ -C₄)-alkyl, Het-thio-(C₁ -C₆)-alkyl, Het-thio-(C₃-C₈)-cycloalkyl, Het-thio-(C₃ -C₈)-cycloalkyl-(C₁ -C₄)-alkyl, where Hetis in each case the radical of a 5- to 7-membered monocyclic or 8- to10-membered bicyclic ring system which can be benzofuzed, aromatic,partially hydrogenated or completely hydrogenated, which can contain, asheteroelements, one, two, three or four different radicals from thegroup N, O, S, NO, SO, and SO₂, which can be substituted by 1 to 6hydroxyl and which is optionally monosubstituted, disubstituted ortrisubstituted as defined for (C₆ -C₁₄)-aryl under a1) and/or by oxo, orare a radical NR¹² R¹³ or NR¹² *R¹³ *, respectively, or, a2) are aradical of the formula VIII or VIII*, respectively,

    R1a--W                                                     (VIII)

    R1a*--W*                                                   (VIII*)

in which R1a and R1a* are defined as are R¹ and R¹ *, respectively,under a1) and W or W* is --CO--, --CS--, O--CO--, --SO₂ --, --SO--,--S--, --NHSO₂ --, --NHCO--, --CH(OH)--, --N(OH)-- or --CO--V--, where Vis a peptide having from 1 to 10 amino acids; or in which R¹ and R¹ *,independently of each other, form, together with R¹¹ or R¹¹ *,respectively, and the atoms carrying the latter, monocyclic or bicyclic,saturated or partially unsaturated, ring systems having 5-12 ringmembers which, in addition to carbon, can also contain 1 sulfur atomwhich can optionally be oxidized to the sulfoxide or sulfone; a3) are aglycosyl radical, preferably a glucofuranosyl or glucopyranosyl radical,which is derived from naturally occurring aldotetroses, aldopentoses,aldohexoses, ketopentoses, ketohexoses, deoxyaldoses, aminoaldoses andoligosaccharides and also their stereoisomers; R² and R² *,independently of each other, are defined as are R¹ and R¹ *,respectively, under a1) or a2), or form, together with R⁴ or R⁴ *,respectively, and the atoms carrying the latter, monocyclic or bicyclic,saturated or partially unsaturated, ring systems having from 5 to 12ring members, or form, together with R³ or R³ *, respectively, and theatoms carrying the latter, cyclic, saturated or partially unsaturated,ring systems having from 3 to 12 ring members; R³ and R³ *,independently of each other, arehydrogen or (C₁ -C₃)-alkyl; R⁴ and R⁴ *,independently of each other, arehydrogen or (C₁ -C₈)-alkyl; R⁵ishydrogen, (C₁ -C₂₀)-alkyl, (C₂ -C₂₀)-alkenyl or alkynyl, (C₇-C₂₀)-arylalkyl or (C₆ -C₂₀)-aryl, (C₃ -C₈)-cycloalkyl which can beoptionally substituted by different radicals from the group hydroxyl,alkoxy, carboxyl, alkanoyloxy, alkoxycarbonyl, F, Cl, Br, I, amino,alkylamino or dialkylamino; an equivalent of a pharmaceuticallytolerated cation, or is a phosphinate prodrug; R⁶ is oxygen or sulfur;R⁷ and R⁷ *, independently of each other, arehydrogen, (C₁ -C₂₀)-alkyl,(C₂ -C₂₀)-alkenyl or alkynyl, (C₆ -C₂₀)-aryl, (C₇ -C₂₀)-arylalkyl, whichcan be optionally substituted by different radicals from the grouphydroxyl, alkoxy, carboxyl, alkanoyloxy, alkoxycarbonyl, F, Cl, Br, I,amino, alkylamino or dialkylamino, or, together, can form a ring having2-6 carbon atoms, R⁸ and R⁸ *, independently of each other, arehydrogenor (C₁ -C₈)-alkyl, or, together with R⁹ or R⁹ *, respectively, and theatoms carrying the latter, form monocyclic or bicyclic, saturated orpartially unsaturated, ring systems having 5-12 ring members; R⁹ andR⁹ * are, independently of each other, defined as are R¹ and R¹ *,respectively, under a1), are hydroxyl or (C₁ -C₈)-alkanoyloxy, or form,together with R¹⁰ or R¹⁰ *, respectively, and the atoms carrying thelatter, cyclic, saturated or partially unsaturated, ring systems havingfrom 3 to 12 ring members; or form, together with R¹¹ or R¹¹ *,respectively, and the atoms carrying the latter, a monocyclic orbicyclic, saturated or partially unsaturated, ring system having 5-12ring members which, in addition to carbon, can also contain 1 sulfuratom which can optionally be oxidized to the sulfoxide or sulfone; orcan contain 1 nitrogen atom, where the ring system can optionally besubstituted by amino; R¹⁰ and R¹⁰ *, independently of each other,arehydrogen or (C₁ -C₆)-alkyl; R¹¹ and R¹¹ *, independently of eachother, arehydrogen, hydroxyl, (C₁ -C₄)-alkanoyloxy, or (C₁ -C₈)-alkyl;R¹², R¹² *, R¹³ and R¹³ *, independently of each other, arehydrogen, (C₁-C₈)-alkyl which can be substituted by amino, (C₁ -C₄)-alkylamino,di-(C₁ -C₄)-alkylamino, mercapto, carboxyl, hydroxyl or (C₁ -C₄)-alkoxy,(C₃ -C₇)-cycloalkyl, (C₁ -C₄)-alkoxycarbonyl, (C₆ -C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁ -C₄)-alkoxycarbonyl which can be substituted in the arylmoiety as described for R¹ or R¹ *, Het or Het-(C₁ -C₄)-alkyl, where Hetis defined as described for R¹ or R¹ *, or where R¹² and R¹³ or R¹² *and R¹³ *, respectively, form, together with the nitrogen atoms carryingthem, monocyclic or bicyclic, saturated, partially unsaturated oraromatic ring systems which also contain, as further ring members inaddition to carbon, 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygenatom, and which can be substituted by (C₁ -C₄)-alkyl, where in the abovecompounds of the formula I, one or more amide groups (--CONH--) of themain chain can be replaced by --CH₂ NR₁₄ --, --CH₂ S--, --CH₂ O--,--OCH₂ --, --CH₂ CH₂ --, --CH═CH-- (cis and trans), --COCH₂ --,--CH(OH)CH₂ --, --CH₂ SO--, --CH₂ SO₂ --, --COO--, --P(O)(OR₁₅)CH₂ --and --P(O)(OR₁₅)NH--, or even by an amide group having reverse polarity(--NHCO--); in which R¹⁴ and R¹⁵, independently of each other,arehydrogen or (C₁ -C₄)-alkyl;and the physiologically tolerated saltsthereof.
 2. A compound of the formula I as claimed in claim 1, whereinthe radicals and symbols with and without asterisk are in each caseidentical.
 3. A compound of the formula I as claimed in claim 1,whereinQ is a radical of the formulae IIa or IIb; Y is oxygen or sulfur;A, A*, D, D*, n, n*, o, o*, p and p* are defined as above; E, E*, F, F*,G and G*, independently of each other, are a natural or unnaturalα-amino acid or α-imino acid; R¹ and R¹ *, independently of each other,a1*) arehydrogen; carboxyl, (C₁ -C₁₂)-alkyl, which is optionallyunsaturated once and which is optionally substituted by up to 2identical or different radicals from the group hydroxyl, (C₁-C₄)-alkoxy, carbamoyl, (C₁ -C₈)-alkanoyloxy, carboxyl, (C₁-C₄)-alkoxycarbonyl, F, amino, (C₁ -C₇)-alkylamino, di-(C₁-C₇)-alkylamino, (C₁ -C₆)-alkoxycarbonylamino benzyloxycarbonyl,benzyloxycarbonylamino, 9-fluorenylmethoxycarbonylamino, (C₁-C₄)-alkylsulfonyl, a radical CONR¹² R¹³ or CONR¹² *R¹³ *, by up tothree phenyl, by up to six hydroxyl, or by up to four (C₁-C₈)-alkanoyloxy; monocyclic or bicyclic (C₃ -C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁ -C₆)-alkyl where the cycloalkyl moiety is in eachcase optionally substituted by one or two identical or differentradicals from the group F, carboxyl, hydroxyl, (C₁ -C₇)-alkoxy, (C₁-C₄)-alkyl, (C₁ -C₄)-alkyloxycarbonyl, amino, (C₁-C₆)-alkoxycarbonylamino, benzyloxycarbonylamino, (C₁ -C₄)-alkylamino,and di-(C₁ -C₄)-alkylamino; (C₆ -C₁₀)-aryloxy-(C₁ -C₆)alkyl, (C₆-C₁₀)-aryl, (C₆ -C₁₀)-aryl-(C₁ -C₆)-alkyl, in which the aryl moiety isin each case optionally substituted by one, two or three identical ordifferent radicals from the group F, Cl, Br, hydroxyl, hydroxy-(C₁-C₄)-alkyl, carboxamido, mono- or di-(C₁ -C₄)-alkylaminocarbonyl, (C₁-C₄)-alkoxy, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxycarbonyl, amino, (C₁-C₄)-alkylamino, di-(C₁ -C₄)-alkylamino, carboxyl, carbamoyl, (C₁-C₄)-alkoxycarbonylamino; Het, Het-(C₁ -C₆)-alkyl, Het-(C₅-C₆)-cycloalkyl, Het-thio-(C₁ -C₄)-alkyl, Het-thio-(C₅ -C₆)-cycloalkyl,where Het is in each case the radical of a 5- to 6-membered monocyclicor 8- to 10-membered bicyclic ring system which can be aromatic,partially hydrogenated or completely hydrogenated, which can contain, asheteroelements, one, two, three or four different radicals from thegroup N, O, S, NO, SO and SO₂, which can be substituted by 1 to 4hydroxyl, and which is optionally monosubstituted or disubstituted asdefined for (C₆ -C₁₀)-aryl under a1) and/or by oxo, or is a radical NR¹²R¹³ or NR¹² *R¹³ *, respectively, or a2*)are a radical of the formulaVIII or VIII*, respectively,

    R1a--W                                                     (VIII)

    R1a*--W*                                                   (VIII*)

in which R1a and R1a* are defined as are R¹ and R¹ *, respectively,under a1*) and W or W* is --CO--, --O--CO--, --SO₂ --, --SO--, --S--,--NHCO-- or --CH (OH)--; or in which R¹ and R¹ *, independently of eachother, form, together with R¹¹ or R¹¹ *, respectively, and the atomscarrying the latter, monocyclic, saturated or partially unsaturated,ring systems having 5-8 ring members which, in addition to carbon, canalso contain 1 sulfur atom which can optionally be oxidized to thesulfoxide or sulfone; a3*)are a glycosyl radical which is defined as inclaim 1; R² and R² *, independently of each other, b1*) arehydrogen,carboxyl, (C₁ -C₁₀)-alkyl which is optionally unsaturated once or twiceand which is optionally substituted by up to 3 identical or differentradicals from the group hydroxyl, (C₁ -C₇)-alkoxy, (C₁ -C₇)-alkylthio,(C₁ -C₇)-alkylsulfinyl, (C₁ -C₇)-alkylsulfonyl, (C₁ -C₇)-alkanoyloxy,carboxyl, (C₁ -C₇)-alkoxycarbonyl, Cl, Br, amino, amidino, guanidino,N,N'-di-(benzyloxycarbonyl)guanidino, carbamoyl, (C₇-C₁₅)-aralkoxycarbonyl, (C₁ -C₅)-alkoxycarbonylamino, (C₇-C₁₅)-aralkoxycarbonylamino, or 9-fluorenylmethoxycarbonylamino; (C₃-C₁₂)-cycloalkyl, (C₃ -C₁₂)-cycloalkyl-(C₁ -C₃)-alkyl, (C₆ -C₁₄)-aryl,(C₆ -C₁₄)-aryl-(C₁ -C₃)-alkyl, where the aryl moiety is in each caseoptionally substituted by one, two or three identical or differentradicals from the group F, Cl, Br, I, hydroxyl, (C₁ -C₇)-alkoxy, (C₁-C₇)-alkyl, (C₁ -C₇)-alkoxycarbonyl, amino and trifluoromethyl; orHet-(C₁ -C₆)-alkyl, where Het is the radical of a 5- or 6-memberedmonocyclic or 9- to 10-membered bicyclic, optionally partially orcompletely hydrogenated, heteroaromatic compound, having at least 1 Catom, 1-4 N atoms and/or 1-2 S atoms and/or 1-2 O atoms as ring members,which is optionally monosubstituted or disubstituted as described forthe aryl moiety in claim 1;or b2*) form, together with R⁴ or R⁴ *,respectively, and the atoms carrying the latter, pyrrolidine orpiperidine which can in each case also be fused with cyclopentyl,cyclohexyl or phenyl, or form, together with R³ or R³ *, respectively,and the atoms carrying the latter, cyclic, saturated or partiallyunsaturated, ring systems having 3-8 ring members; R³ and R³ *,independently of each other, arehydrogen, methyl or ethyl; R⁴ and R⁴ *,independently of each other, arehydrogen, (C₁ -C₄)-alkyl; R⁵ ishydrogen,(C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or alkynyl, (C₇ -C₂₀)-arylalkyl, (C₆-C₁₀)-aryl, an equivalent of a pharmaceutically tolerated cation or isglyceryl ester, 1,2-difatty acid glyceryl triester, O-acyloxyalkyl esteror 1-methyl-2-nitroethyl ester, R⁶ isoxygen or sulfur; R⁷ is defined asdescribed in claim 1, R⁸ and R⁸ *, independently of each other,arehydrogen, (C₁ -C₈)-alkyl or form, together with R⁹ or R⁹ *,respectively, and the atoms carrying the latter, pyrrolidine orpiperidine which can in each case be additionally fuzed withcyclopentyl, cyclohexyl or phenyl; R⁹ and R⁹ *, independently of eachother, are defined as are R² or R² *, respectively, under b1*), or are(C₁ -C₈)-alkanoyloxy, or form, together with R¹⁰ or R¹⁰ *, respectively,and the atoms carrying the latter, cyclic, saturated or partiallyunsaturated, ring systems having from 5 to 12 ring members; or form,together with R¹¹ or R¹¹ *, respectively, and the atoms carrying thelatter, a monocyclic or bicyclic, saturated or partially unsaturated,ring system having 5-12 ring members which, in addition to carbon, canalso contain 1 sulfur atom which can optionally be oxidized to thesulfoxide or sulfone; R¹⁰ and R¹⁰ *, independently of each other,arehydrogen or (C₁ -C₄)-alkyl; R¹¹ and R¹¹ *, independently of eachother, arehydrogen, hydroxyl, (C₁ -C₄)-alkanoyloxy or (C₁ -C₄)-alkyl;R¹², R¹² *, R¹³ and R¹³ *, independently of each other, arehydrogen, (C₁-C₈)-alkyl which can be substituted by amino, (C₁ -C₄)-alkylamino,di-(C₁ -C₄)-alkylamino, carboxyl, hydroxyl or (C₁ -C₄)-alkoxy, (C₁-C₄)-alkoxycarbonyl, (C₆ -C₁₀)-aryl which can be substituted asdescribed for R¹ or R¹ *, respectively (C₆ -C₁₀)-aryl-(C₁-C₄)-alkoxycarbonyl, Het or Het-(C₁ -C₄)-alkyl, where Het is defined asdescribed for R¹ or R¹ *, respectively,where, in the above compounds ofthe formula I, one or more amide groups (--CONH--) of the main chain canbe replaced by a group comprising --CH₂ NR¹⁴ --, --CH₂ O--, --OCH₂ --,--CH₂ CH₂ --, --COCH₂ --, --CH(OH)CH₂ -- or --COO--, or else by an amidegroup having reversed polarity (--NHCO--); R¹⁴ ishydrogen or (C₁-C₄)-alkyl;and the physiologically tolerated salts thereof.
 4. Acompound of the formula I as claimed in claim 1, whereinQ is a radicalof the formulae IIa or IIb; Y, A, A*, D, D*, n, n*, o and o* are definedas in claim 1, p and p* are 1; R¹ and R¹ *, independently of each other,arehydrogen, carboxyl, (C₁ -C₁₀)-alkyl, (C₃ -C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁ -C₁₀)-alkyl, phenyl-(C₁ -C₈)-alkyl which can besubstituted in the phenyl moiety as described for phenyl in claim 3,triphenyl-(C₁ -C₄)-alkyl, optionally protected mono- or di-amino-(C₁-C₁₀)-alkyl or amino-(C₆ -C₁₀)-aryl-(C₁ -C₄)-alkyl or amino-(C₃-C₁₀)-cycloalkyl-(C₁ -C₄)-alkyl, mono-, di-, tri-, tetra-, penta- orhexa-hydroxy-(C₁ -C₁₀)-alkyl or -alkanoyl, (C₁ -C₄)-alkoxy-(C₁-C₁₀)-alkyl, (C₁ -C₄)-alkoxycarbonyl-(C₁ -C₁₀)-alkyl, (C₁-C₈)-alkylsulfonyl, (C₁ -C₈)-alkylsulfinyl, mono-, di- or tri-hydroxy-(C₁ -C₈)-alkylsulfonyl, mono-, di- or tri -hydroxy-(C₁-C₈)-alkylsulfinyl, mono-, di-, tri- or tetra-(C₁ -C₈)-alkanoyloxy-(C₁-C₁₀)-alkyl, (C₁ -C₁₁)-alkanoyl, optionally protected amino-(C₁-C₁₁)-alkanoyl, di-(C₁ -C₇)-alkylamino-(C₂ -C₁₁)-alkanoyl, (C₁-C₉)-cycloalkylcarbonyl, amino-substituted (C₃ -C₉)-cycloalkylcarbonyl,amino-substituted (C₃ -C₉)-cycloalkylsulfonyl, (C₆ -C₁₀)-aryl-(C₂-C₇)-alkanoyl, (C₆ -C₁₀)-aryl-(C₂ -C₇)-alkanoyl, benzoyl,benzenesulfonyl or (C₆ -C₁₀)-aryl-(C₁ -C₄)-alkylcarbonyl or -sulfonylwhich is optionally substituted by amino, halogen, (C₁ -C₇)-alkyl, (C₁-C₇)-alkoxy or (C₁ -C₇)-alkoxycarbonyl, (C₁ -C₁₀)-alkoxycarbonyl,substituted (C₁ -C₁₀)-alkoxycarbonyl, (C₆ -C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl, (C₆ -C₁₀)-aryl-(C₁ -C₈)-alkyl, (C₃-C₁₀)-cycloalkyl-(C₁ -C₈)-alkyl or (C₁ -C₁₀)-alkyl which are substitutedby optionally protected amino or hydroxyl, 9-fluorenylmethoxycarbonyl,ketohexosyl, ketopentosyl, deoxyhexoketosyl, deoxypentoketosyl,aldohexosyl, aldopentosyl, deoxyhexoaldosyl, deoxypentoaldosyl,2-amino-2-deoxyhexosyl, 2-acetamido-2-deoxyhexosyl, lactosyl or maltosylwhere the linked sugars can be present in the pyranose or furanose form,Het-(C₁ -C₆)-alkyl, Het-carbonyl or -sulfonyl, Het-(C₁-C₆)-alkylcarbonyl or -sulfonyl, Het-mercapto-(C₁ -C₆)alkylcarbonyl or-sulfonyl, where Het is in each case furyl, thienyl, benzothienyl,benzodioxolanyl, pyrrolyl, imidazolyl, isoxazolyl, thiazolyl, pyrazolyl,triazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl,pyrrolidyl, piperidyl, piperazinyl, morpholino, thiomorpholino,tetrahydrofuryl, tetrahydropyryl, tetrahydrothienyl, indolyl, quinolylor isoquinolyl, where these radicals can also be substituted by one ortwo identical or different radicals from the group (C₁ -C₄)-alkyl, (C₁-C₄)-alkoxy, (C₁ -C₄)-alkoxycarbonyl, (C₁ -C₄)-alkoxycarbonylamino,hydroxyl, amino, mono- or di-(C₁ -C₄)-alkylamino and oxido; R² and R² *,independently of each other, arehydrogen, carboxyl, (C₁ -C₈)-alkyl whichis optionally substituted by up to 2 identical or different radicalsfrom the grouphydroxyl, (C₁ -C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁-C₄)-alkylsulfinyl, (C₁ -C₄)-alkylsulfonyl, (C₁ -C₄)-alkanoyloxy,carboxyl, (C₁ -C₄)-alkoxycarbonyl, amino, amidino, guanidino,N,N'-di-(benzyloxycarbonyl)guanidino, carbamoyl, (C₆ -C₁₀)-aryl-(C₁-C₃)-alkoxycarbonyl, (C₁ -C₅)-alkoxycarbonylamino, (C₆ -C₁₀)-aryl-(C₁-C₃)-alkoxycarbonylamino, or (C₃ -C₁₀)-cycloalkyl, (C₃-C₁₀)-cycloalkyl-(C₁ -C₃)-alkyl, (C₁ -C₄)-alkyl-(C₃ -C₁₀)-cycloalkyl-(C₁-C₃)-alkyl, (C₆ -C₁₀)-aryl, (C₆ -C₁₀)-aryl-(C₁ -C₃)-alkyl where the arylmoiety is in each case optionally substituted by one, two or threeidentical or different radicals from the group F, Cl, Br, hydroxyl, (C₁-C₄)-alkoxy, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxycarbonyl and amino, orHet-(C₁ -C₄)-alkyl where Het is defined as in the case of R¹ or R¹ *,respectively; R³ and R³ *, independently of each other, are,hydrogen ormethyl; R⁴ and R⁴ *, independently of each other, arehydrogen or methyl;R⁵, R⁶ and R⁷ are defined as described in claim 3; R⁸ and R⁸ *,independently of each other, arehydrogen, methyl, ethyl or n-propyl, orform, together with R⁹ or R⁹ *, respectively, and the atoms carrying thelatter,a 1,2,3,4-tetrahydroisoquinoline or a 2-azabicyclooctaneskeleton; R⁹ and R⁹ *, independently of each other, are defined as areR² or R² *, respectively, or are (C₁ -C₈)-alkanoyloxy or form, togetherwith R¹⁰ or R¹⁰ *, respectively, and the atoms carrying the latter,cyclic ring systems having from 5 to 7 ring members; or form, togetherwith R¹¹ or R¹¹ *, a thiochromane system whose sulfur atom canoptionally be oxidized to the sulfone; R¹⁰ and R¹⁰ *, independently ofeach other, arehydrogen or methyl; R¹¹ and R¹¹ * are defined asdescribed in claim 3;where, in the above compounds of the formula 1, oneor more amide groups (--CONH--) of the main chain can be replaced asdefined in claim 3; R¹⁴ ishydrogen or methyl;and the physiologicallytolerated salts thereof.
 5. A compound of the formula I as claimed inclaim 1, whereinQ is a radical of the formula IIa; R¹ and R¹ *,independently of each other, arehydrogen, carboxyl, (C₁-C₈)-alkylsulfonyl, (C₁ -C₈)-alkylsulfinyl, (C₁ -C₈)-mono-, di- ortri-hydroxyalkylsulfonyl, hydroxy-(C₁ -C₁₀)-alkanoyl, mono-, di-, tri-or tetra-hydroxy-(C₁ -C₄)-alkyl, (C₁ -C₈)-alkanoyloxy-(C₁-C₁₀)-alkyl,
 1. 2-diacetoxyethyl,1,2,3-triacetoxypropyl, (C₁-C₁₁)-alkanoyl, amino-(C₁ -C₁₁)-alkanoyl, N-(C₁-C₄)-alkoxycarbonylamino-(C₁ -C₈)-alkyl, di-(C₁ -C₇)-alkylamino-(C₂-C₁₁)-alkanoyl, (C₃ -C₉)-cycloalkylcarbonyl, amino-(C₃-C₈)-cycloalkylcarbonyl, amino-(C₃ -C₈)-cycloalkylsulfonyl, phenyltriphenyl-(C₁ -C₂)-alkyl, (C₆ -C₁₀)-aryl-(C₁ -C₄)-alkyl, (C₆-C₁₀)-aryl-(C₂ -C₇)-alkanoyl, (C₆ -C₁₀)-aryloxy-(C₂ -C₇)-alkanoyl,benzoyl or -benzenesulfonyl which are optionally substituted by halogen,amino, (C₁ -C₇)-alkyl, (C₁ -C₇)-alkoxy or (C₁ -C₇)-alkoxycarbonyl,benzylsulfonyl, benzylsulfinyl or benzylthio which are optionallysubstituted by halogen, amino, (C₁ -C₇)-alkyl, (C₁ -C₇)-alkoxy or (C₁-C₇)-alkoxycarbonyl, amino, (C₁ -C₄)-alkoxycarbonylamino, (C₁-C₁₂)-alkanoyl which is substituted by hydroxyl or amino and optionallyby phenyl or cyclohexyl, (C₆ -C₁₀)-aryl- or (C₃ -C₁₀)-cycloalkyl-(C₁-C₄)-alkyl or (C₁ -C₈)-alkyl which are substituted by optionallyprotected amino, (C₁ -C₁₀)-alkoxycarbonyl, substituted (C₁-C₁₀)-alkoxycarbonyl, (C₆ -C₁₄)-aryl-(C₁ -C₆)-alkoxycarbonyl,9-fluorenylmethoxycarbonyl, 1-deoxyhexoketosyl or 1-deoxypentoketosyl,hexosyl or pentosyl, 6-deoxyhexosyl, aminosugar residues, lactosyl,maltosyl, where the linked sugars can be present in the pyranose or thefuranose form,Het, Het-carbonyl or Het-sulfonyl, Het-(C₁ -C₆)-alkyl,Het-(C₁ -C₆)-alkanoyl Het-(C₁ -C₆)-alkylsulfonyl, Het-mercapto-(C₁-C₃)-alkylcarbonyl,where Het is in each case pyrrolyl, imidazolyl,pyridyl, pyrimidyl, pyrrolidyl, piperidyl, quinolyl, isoquinolyl ormorpholino, where the latter can also be substituted by one or twoidentical or different radicals from the group (C₁ -C₄)-alkyl, (C₁-C₄)-alkoxycarbonyl, (C₁ -C₄)-alkoxycarbonylamino, hydroxyl, amino ormono- or di-(C₁ -C₄)-alkylamino; R² and R² *, independently of eachother, arehydrogen, carboxyl, methyl, ethyl, isopropyl, n-propyl,n-butyl, isobutyl, sec-butyl, pentyl or hexyl, cyclohexyl,cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl,4-methylcyclohexylmethyl, 1-decahydronaphthylmethyl or2-decahydronaphthylmethyl, phenyl, benzyl, 2-phenylethyl,1-naphthylmethyl or 2-naphthylmethyl, 2-methylbenzyl, 3-methylbenzyl or4-methylbenzyl, 2,4,6-trimethylbenzyl, 4-tert-butylbenzyl,4-tert-butoxybenzyl, 4-hydroxybenzyl, 4-methoxybenzyl,2,4-dimethoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl,(benzodioxolan-4-yl)methyl, 4-chlorobenzyl, hydroxymethyl,1-hydroxyethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethylor2-(4-pyridyl)ethyl, 2-thienylmethyl or 3-thienylmethyl,2-(2-thienyl)ethyl or 2-(3-thienyl)ethyl, indol-2-ylmethyl orindol-3-ylmethyl, (1-methylimidazol-4-yl)methyl, imidazol-4-ylmethyl orimidazol-1-ylmethyl, 2-thiazolylmethyl, 3-pyrazolylmethyl,4-pyrimidylmethyl, 2-benzo[b]thienylmethyl or 3-benzo[b]thienylmethyl,2-furylmethyl, 2-(methylthio)ethyl, 2-(methylsulfinyl)ethyl,2-(methylsulfonyl)ethyl, R³, R³ *, R⁴, R⁴ *, R¹⁰ and R¹⁰ * are hydrogen;R⁵ ishydrogen, (C₁ -C₆)-alkyl or an equivalent of a pharmaceuticallytolerated cation; R⁶ isoxygen; R⁸ and R⁸ *, independently of each other,arehydrogen or form, together with R⁹ or R⁹ *, respectively, and theatoms carrying the latter, a 1,2,3,4-tetrahydroisoquinoline or2-azabicyclooctane skeleton; R⁹ and R⁹ *, independently of each other,are defined as are R² or R² *, respectively, or arehydroxyl, acetoxy,tert-butoxymethyl, 3-guanidinopropyl, carbamoylmethyl or carbamoylethyl,carboxymethyl or carboxyethyl, mercaptomethyl,(1-mercapto-1-methyl)ethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl or4-aminobutyl, N, N-dimethylamino,N,N'-di(benzyloxycarbonyl)guanidinopropyl, 2-benzyloxycarbonylethyl,benzyloxycarbonylmethyl or tert-butylsulfonylmethyl or4-benzylcarbonylaminobutyl; R¹¹ and R¹¹ *, independently of each other,arehydrogen, hydroxyl or acetoxy;where, in the above compounds of thisinvention, one or more amide groups (--CONH--) of the main chain can bereplaced by --CH₂ NR₁₄ -- or --CH(OH)CH₂ --; R¹⁴ ishydrogen ormethyl;and the physiologically tolerated salts thereof.
 6. A compound ofthe formula I as claimed in claim 1, whereinQ is a radical of theformula IIa; R¹ and R¹ *, independently of each other, arehydrogen,carboxyl, (C₁ -C₈)-alkylsulfonyl, (C₁ -C₈)-mono- ordi-hydroxyalkylsulfonyl, mono-, di- or tri-hydroxy-(C₁ -C₃)-alkyl, (C₁-C₈)-alkanoyl, (C₆ -C₁₀)-aryloxy-(C₁ -C₄)-alkanoyl, (C₆ -C₁₀)-aryl-(C₁-C₄)-alkanoyl, (C₁ -C₈)-alkoxycarbonyl (C₆ -C₁₀)-aryl-(C₁-C₄)-alkoxycarbonyl, 9-fluorenylmethoxycarbonyl, (C₁-C₄)-alkanoyloxy-(C₁ -C₆)-alkyl, 1,2-diacetoxyethyl,1,2,3-triacetoxypropyl, phenyl, triphenylmethyl, (C₆ -C₁₀)-aryl-(C₁-C₄)-alkyl, benzenesulfonyl which is optionally substituted by halogen,amino, (C₁ -C₄)-alkyl or methoxy, benzylsulfonyl, benzylsulfinyl orbenzylthio which is optionally substituted by halogen, amino, (C₁-C₄)-alkyl or methoxy, Het, Het-carbonyl or Het-sulfonyl, Het-(C₁-C₄)-alkylsulfonyl, Het-(C₁ -C₄)-alkanoyl, Het-mercapto-(C₁-C₃)-alkylcarbonyl, where Het is in each casepyrrolyl, imidazolyl,pyridyl, pyrimidyl, pyrrolidyl, piperidyl, quinolyl, isoquinolyl ormorpholino, where this radical can also be substituted by one or twoidentical or different radicals from the group methyl, amino and (C₁-C₄)-alkoxycarbonylamino, amino-(C₃ -C₆)-cycloalkylcarbonyl, (C₁-C₈)-alkanoyl which is substituted by hydroxyl and amino and optionallyby phenyl or cyclohexyl, phenyl- or cyclohexyl-(C₁ -C₆)-alkyl which issubstituted by optionally protected amino, amino, (C₁-C₄)-alkoxycarbonylamino, benzyloxycarbonylamino, 1-deoxyhexoketosyl or1-deoxypentoketosyl, hexosyl or pentosyl, where the linked sugars can bepresent in the pyranose or the furanose form, R² and R² *, independentlyof each other, arehydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl,isobutyl, sec-butyl, pentyl or hexyl, cyclopentylmethyl orcyclohexylmethyl, 4-methylcyclohexylmethyl, phenyl, 2-phenylethyl,1-naphthylmethyl or 2-naphthylmethyl, 2-methylbenzyl, 3-methylbenzyl or4-methylbenzyl, 2,4,6-trimethylbenzyl, 4-tert-butylbenzyl,4-methoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl,2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, or2-(4-pyridyl)ethyl, R³, R³ *, R⁴, R⁴ *, R¹⁰ and R¹⁰ * are hydrogen; R⁵and R⁶ are defined as described in claim 5; R⁸ and R⁸ *, independentlyof each other, arehydrogen or form, together with R⁹ or R⁹ *,respectively, and the atoms carrying the latter, a1,2,3,4-tetrahydroisoquinoline or 2-azabicyclooctane skeleton; R⁹ and R⁹*, independently of each other, are defined as R⁹ and R⁹ *,respectively, are described in claim 5; R¹¹ and R¹¹ *, independently ofeach other, arehydrogen; hydroxyl or acetoxy;where, in the abovecompounds of this invention, one or more amide groups (--CONH--) of themain chain can be replaced by --CH₂ NH-- or --CH(OH)CH₂ --;and thephysiologically tolerated salts thereof.
 7. A compound of the formula Ias claimed in claim 1, whereinthe radicals and symbols with and withoutan asterisk are in each case identical, Q is a radical of the formulaIIa, Y is oxygen, A is a radical of the formula IV in whichE, F or G areGly, Ala, Val, Leu, Ile, Nva, Nle, Phe, Tyr, Asp or Glu,and n+o+p is 0or 1, D is R¹ or a radical of the formulae V or VI, R¹ is hydrogen, (C₁-C₆)-alkylsulfonyl, (C₆ -C₁₀)-aryl-(C₁ -C₂)-alkyl, triphenylmethyl, (C₁-C₆ )-alkoxycarbonyl, (C₆ -C₁₀)-aryl-(C₁ -C₂)-alkanoyl, (C₆-C₁₀)-aryloxy-(C₁ -C₂)-alkanoyl, Het-carbonyl or (C₆ -C₁₀)-aryl-(C₁-C₂)-alkoxycarbonyl, R² is hydrogen, phenyl, benzyl, methyl, ethyl,isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, pentyl orcyclohexylmethyl, R³, R⁴, R⁸, R¹⁰ and R¹¹ are hydrogen, R⁵ is hydrogenor (C₁ -C₆)-alkyl, R⁶ is oxygen, and R⁹ is hydrogen, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, benzyl, carboxymethyl,carboxyethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(methylthio)ethyl,2-(methylsulfinyl)ethyl, 2-(methylsulfonyl)ethyl, indol-2-ylmethyl orindol-3-ylmethyl,and the physiologically tolerated salts thereof.
 8. Acompound of the formula I as claimed in claim 1, whereinthe radicals andsymbols with and without an asterisk are in each case identical, Q is aradical of the formula IIa, Y is oxygen; A is a radical of the formulaIV, whereE, F or G is Val, Phe, Ile or Asp, and n+o+p is 0 or 1; D is R¹or a radical of the formulae V or VI; R¹ is hydrogen, (C₁-C₆)-alkylsulfonyl, phenyl-(C₁ -C₂)-alkyl, triphenylmethyl, (C₁-C₆)-alkoxycarbonyl or phenyl-(C₁ -C₂)-alkoxycarbonyl, R² is hydrogen,phenyl, benzyl, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl,sec-butyl, pentyl or cyclohexylmethyl, R³, R⁴, R⁸, R¹⁰ and R¹¹ arehydrogen, R⁵ is hydrogen or (C₁ -C₄)-alkyl, R⁶ is oxygen, and R⁹ ishydrogen, isopropyl, sec-butyl, benzyl, carboxymethyl, 1-naphthylmethyl,2-(methylthio)-ethyl or indol-2-ylmethyl,and the physiologicallytolerated salts thereof.
 9. A process for preparing a compound of theformula I as claimed in claim 1, wherein a fragment having a terminalcarboxyl group, or a reactive derivative of this fragment, is coupled toa corresponding fragment having a free amino group, (a) protectivegroup(s) which has/have, where appropriate, been temporarily introducedto protect further functional groups is/are eliminated, and the compoundthus obtained is, where appropriate, converted into its physiologicallytolerated salt.
 10. A composition containing a compound of the formula Ias claimed in claim 1 together with a pharmaceutically acceptablecarrier.